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Full text of "Opening Statements Before the Committee on Appropriations"




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U. S. DEPMTMENT OF HEALTH, EDUCATION, AND WELFARE 

PUBLIC IffiALTH SERVICE 
OPERATING EXF'ENSES . NATIONAL INSTITUTES OF HEALTH 

(statement of Dr. Uilliara H, Sebrell, Jr., Director of the National Institutes 
of Health, before the Labor-Health, Education, and Welfare Subcommittee of 
the Committee on Appropriations) 

Post"War Medical Research in the U.S« 
As a Nation, we are nov/ in the fifth year of an expanded medical 
research effort. During that period there has been a most remarkable grov/th 
of both private and public support for medical research and for training 
medical research manpomer. 

This upsurge of support is concrete evidence that the American people 
have firmly endorsed both the humanitarian and the direct economic gains to 
be achieved ultimately by medical research* ITe have, as a Nation, adopted 
by the force of logic and public opinion two policies: 

Capable investigators should be supplied nith the funds they need to 
exploit their ideas fully. 

Additional manpo?/er of high caliber should be trained to expand our 
National research capacity* 

In the evolution of these tno lines of policy, the Congress has been 
a leader, both through establishing the structure for research in the form 
of National medical research institutes and through providing substantial 
appropriations to make the machinery operative not only in these institutes 
but also in non-governmental research and teaching institutions. 

In the light of these developments, vie need not take time to reiterate 
the significance of the disease problems in economic terms and in terms of 
suffering among individuals and their families, .. 



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The time has come when it is no longer valid merely to complain of the 
problems created by chronic disease; we should be able to point to concrete 
advances achieved over a wide front. The concentration of brains and 
facilities over this period leads to a legitimate expectation of solid 
advance . 

These advances are being made, and at every level, from fundamental 
laboratory work to direct clinical application. 

The Institute Directors will indicate in some detail the recent 
accomplishments of investigators throughout the Nation in their respective 
fields of categorical responsibility, but a brief check list here will indi- 
cate a tremendous vitality and forward surge in a wide array of fields. 

In the field of mental diseases, there are firm leads that begin to 
explain some mental disorders in terms of biochemical differences between 
the normal and the mentally ill person. This is a general development of 
the utmost significance. At the same time, advances on the psychiatric and 
psychological fronts are opening the way to more precise early identification 
of those who will and those who will not respond to established treatment 
procedures. The development of reliable tests in this field will effectively 
multiply the efficiency of our limited manpower and treatment facilities. 

In heart disease, the discovery of new anti-clotting substances has 
resulted in the saving or prolonging of many lives. Drugs have been 
developed which can stop often fatal arrhythmia-irregular heart beats — 
and a more precise understanding of cardiac failia-e has permitted the 
development of more rational treatment. This latter advance has not only 
increased the life span of countless cardiacs but has returned vast 
numbers to comfortable and profitable employment. 



- 3 - 
In the neurological field, significant progress against epilepsy as 
a significant disease is presaged by the first fruits of research - the 
discovery of new drugs, advances in surgery, and a beginning understanding 
of basic biochemical defects which characterize this condition. The sacred 
scientific trviism that severed nerves in the central nervous system cannot 
grow back together has been disproved, a discovery that opens a whole new 
field of study of great potential practical importance. 

In the cancer field, a positive, simple test for cervical cancer has 
been found. Of particular importance in this regard is the developing con- 
viction, based on sound observations, that a detectable pre-invasive condition 
is the rule rather than the exception. The disappearance of this form of 
cancer as a serious heialth threat now depends solely on early detection and 
treatment. Radioactive isotopes are providing both better diagnostic 
techniques and better treatment for certain other forms of cancer. 

In the field of arthritis, rheumatism and other metabolic diseases, 
use of ACTH and cortisone as treatments has been widely publicized, as have 
some of their deficiencies. Equally stimulating to medical scientists is 
the avenue of study that these and related chemicals have opened up— 
studies directed towards an understanding of the underlying causes of the 
wide array of these related diseases. 

In the field of microbiology, recent advances have centered attention 
on viruses and bacteria as the cause of some chronic and degenerative diseases 
as well as acute infections. This is quite a new approach to the significance 
of microbiological agents, and one of tremendous potential significance. 

In short, the first big National push in medical research is beginning 
to pay off even within a five-year time span. And five years is a short 



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period in medical research. It can be confidently predicted that the flow of 
productive findings will grow if medical research is supported amply and 
wisely. 

It can also be predicted that many answers ^^^ill not be found for 
decades. This is not a cause for despair, for experience has already amply 
shown that very real progress in saving lives can be made before ultimate causes 
are known. 

In reviei-iing the general status of irBdical research and the recent ad- 
vances, one of the developments that emerges most clearly is the rapid ex- 
tension of productive biochemical and biophysical studies into the medical and 
biological fields. Medical research is coming of age as a quantitative science. 
There is perhaps no more fundamental trend in medical research, and no trend 
which it is more important to encourage. 

This development must be nurtured by funds, for equipment and 
competencies from the physical sciences which are essential to these studies are 
e:q)ensive. It must be nurtured by patience, for the studies are almost 
infinitely complex. It must be nurtured by proper organization for reseairch, 
because the final fruition of medically related research in the physical 
sciences is through a productive partnership with clinical research. 

Against this background of general National developments in medical 
research, we can assess developments in the .programs of the National Institutes 
of Health, 



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MAJOR PROGRAii DEVELOPI'fcNTS AT THE 
NATIONAL IMSTITUILS OF HEALTH, F.Y. 195U 

Development of Gap Areas — Neurology and Blindness j and Arthritis 

In establishing National medical research Institutes, Congress assumed 
that by setting up an organization and providing funds, research in lagging 
areas could be stimulated. 

It is gratifying to report that this assumption has proved to be sound 
in the fields of Neurology and Blindness, and Arthritis and Metabolic Diseases, 

A major program development has been the rapid maturing of the NeuroloQr 
and Blindness Institute to achieve a dimension which begins to approach the 
importance of the problem. You will recall that this Institute was established 
in 1950 and received its first appropriation in 195l« Today, it has gathered 
together a brilliant young staff and is already conducting and supporting 
significant studies in epilepsy, multiple sclerosis, cerebral palsy, and the 
other neurological and sensory disorders. The initiative and drive of this 
group has been one of the high points of the year. 

At the same time, as Dr, Bailey will report in detail, the entire field 
of neurological research throughout the Nation has been encouraged and 
invigorated. 

And all of this has gone forward not tlirough Federal direction or control 
of individuals, institutions or organizations, but through a close collaborative 
effort, . 

A comparable development has taken place in the Arthritis Institute, 
In spite of the enormous importance of the rheumatic diseases (there are now 



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about 10 million victims of arthritis and rheumatism in this country), the 
public and to a degree the professional world was apathetic about these 
diseases. Then, in quick succession, there came a series of events which 
reversed the trends, The Arthritis and Rheumatism Foundation was established 
to raise funds and lead the way in professional and public education. The 
National Research Council set up a National scientific committee to assess 
progress, problems and gaps in the field, Ihen there was the dramatic 
annoiincement of the discovery of cortisone and ACTH» Finally, under the 
Omnibus ifedical Research Act in 1950 - the National Institute of Arthritis 
and Metabolic Diseases was established. In this last three years, using 
revolutionary research approaches and strengthened by strong private and 
public cooperation, it has become eviaent that this field, like neurology, 
has come into its own. Just several months ago there was held at Bethesda 
the first Ifetional symposium ever to be held on research and research training 
in the arthritis and rheumatism field. 

Initial Operations in the Clinical Center 

One of the major program developments at the National Institutes of 
Health, as you gentlemen have good reason to know, has been the opening and 
initial occupancy of the Clinical Center. I will not attempt here to 
recapitulate what this facility has meant to our research program by making 
it possible for us to integrate laboratory and clinical investigations. 
Suffice it to say that the mere existence of this structure on our campus has 
had implications that reach to the very roots of our scientific programs. 

As might be anticipated, we have had to pay a great deal of attention 
during the past fiscal year to the sheer mechanics of moving into the Clinical 



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Center. We have been concerned with such things as the timing of purchasing 

supplies and equipment, planning space occupancy to encourage integrated 

research effort, establishing the policies governing care of patients and their 

relationships with the research environment, adjusting laboratory design to 

meet the specialized needs of investigators who were not employed when the 

initial plans were made, and re-planning occupancy, purchasing, and staffing 

schedules when contractors have failed to meet specifications or deadlines. 

These may appear to be matters of detail, but we have found that the 
satisfactory resolution of a vast array of details is in practice the only 
way we can progress towards ovir general objectives. 

The entire staff has worked hard and has been most cooperative in 
bearing with the inevitable delays and frustrations that are involved in such 
a complicated undertaking. In the face of these problems, patients have been 
brought into the Center, the medical care provided them has been excellent, 
and clinical research has begun in all Institutes. 

One of the most important elements of our work related to the Clinical 
Center has been the establishment of good working relations with physicians in 
private practice, professional groups, and medical institutions. The good 
will and support of these groups is important in the referral of patients, 
in the use of consultants, and —most important— in the ability to establish 
and maintain the many kinds of formal and informal cooperative working 
relationships which are the heart of any successful medical undertaking. 

There are more than a hundred study patients in the Clinical Center 

today. We anticipate that there may be over 200 by July 1. There is 
virtually no way in which this research facility resembles a general 



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hospital (in which the patient day costs can be accurately predicated) save 
in the quality of medical care we provide. There the similarity ends. The 
research design may demand specieil diet, frequent tests, extra nurses, 
expensive medicinals, total isolation — all factors which might be 
essential to research but serve to render valueless any presimptive base- 
line data seeking a standard by which to convert dollars into patients. 
It might not be amiss for me to reiterate that in the Clinical Center, the 
welfare of the patient comes first. It is to my best interest and that of 
the scientific staff to fill the Clinical Center beds with patients and 
keep them filled, to the limit of our program needs and the resources 
available to us. But without experience data, I cannot and will not 
stretch the limits of good medical care and disrupt the standards of 
good research practice in order to meet a ratio of dollars to beds. 



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RESEARCH GRANTS . RESEARC H TRATNTOO, ftAi p pTS^ASE CONTROL 
I. Research Grants 

The basic, tested policies underlying the research grant programs 
have remained basically unaltered. 

We plan to continue support, not only to clinical investigations 
and research directly applicable to medicine, but also to studies which 
are relevant to underlying problems but not immediately applicable to 
medicine. We consider this approach to be so important that - in addition 
to giving it support from the programs of the various Institutes - we have 
a program under the Division of Research Grants directed especially to 
support of basic studies which have a direct relationship to medicine 
as a whole instead of to single disease categories. 

We initiate large- scale coordinated research programs when there 
is a firm scientific consensus that this approach is profitable. 

We continue to rely heavily upon the judgment of university and 
other non-Federal scientists in assessing the worth of proposed projects, 
and particularly the caliber of men. We continue to seek general policy 
advice from National Advisory Councils. 

The esteem in which the program is held in the scientific and 
academic worlds continues to be a source of satisfaction to us, as it 
must be to those Committees of Congress which have sponsored our enabling 
legislation and assumed our continuing support of research and research 
training by establishing our level of expenditure. 

This is not to say that we do not face problems. We have some 
very real ones. For example, we are continually assessing the extent to 






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which the year-to-year project grants provide the kind of long-term 
stability needed for research. We have worked out means of providing 
reasonable stability, and are constamtly considering modifications to 
make the programs more satisfactory. 

As another example, we have been seriously considering whether we 
are compensating institutions adequately for the costs that they incur 
when we give their staffs research support. This is the perplexing 
"indirect cost" problem that has been with us since the program began. 
We are proposing a policy change during the coming year that will be 
discussed when we outline the prospects for fiscal year 1955. 

I I . Man ppwer Training — Fellowships, Teaching Grants, and Traini ng Gran t^ 

In common with all scientific fields, medical research faces the 
prospect of shortages in the future unless training now is accelerated. 

Two considerations are particularly significant in the manpower 
picture in medicine. First, the advance of medical research has been 
80 rapid that specific training is reqxiired to bring the findings to 
the point of application. Second, there is an extreme shortage of 
people in specific fields — of which mental health is perhaps the 
outstanding example. 

In combination, the fellowship, teaching grant and training 
grant programs are designed to meet these problems. The Institute 
Directors will indicate the specific manpower problems faced in their 
areas of interest, and the manner in which the manpower programs are 
tailored to meet the needs of specific fields. 



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III. Control Grants 

It is becoming increasingly clear that much chronic disease 
which will strike millions of people can be dealt with effectively 
if the existence of the disease can be found early enough. EvBn without 
a full knowledge of cause, we now know more about how to halt the 
progress of meiny chronic diseases than is being fully applied. 

The control grants are our effort to close the gap between 
scientific knowledge and application of findings to patients. 

In this area, too, the Institute Directors will tell you 
specifically what the control measiores are accomplishing. 



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PROGRAM DEVELOPMENTS AT N.I«H. - FISCAL YEAR 19gg 
THE 1955 BUDGET PROPOSALIK BROAD OUTLIl^ 



While the National Institutes of Health budget is complicated in detail, 
the essentials of program policy underlying the figures are simple. 

The 1955 budget proposes that the total research grants, research train- 
ing, and disease control areas be financed at a somewhat lower level than in 
195U — $l|6»3 million as compared with ^5^8,6 million. 

In the direct operations of the National Institutes of Health, the 1955 
budget is at the 1951^ level, except for increases required primarily for the 
increased patient load and other research facilities in the Clinical Center 
contemplated in 1955i 

These generalizations do not apply uniformly among all the Institutes; 
the differences will be covered when the Directors explain the essentials of 
their 1955 budgets. 

The Year Ahead at the N,I,H. Laboratories 

■'■ • The Unique Opportunity and the Unique Problems 

The coming fiscal year is a critical one in the development of the 
National Institutes of Health, We are attempting to work out a new approach to 
medical research— integration of laboratory research with research on patients 
on a scale never before attempted. Never before in the history of medicine has 
it been possible to bring together in one place the full array of diverse talent 
that modern medical research requires. 

We owe an incalculable debt to Congress not only for making available the 
funds required for this pioneering enterprise, but also for establishing the 



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medical research Institutes that give us a series of well-rounded frameworks on 
which to build our programs. 

Our responsibility, which we feel most keenly, is to make the most of 
the unique opportunity that has been given to us. Our central objective is 
to set the general policies that i^rill result in the greatest volume of re- 
search of the highest caliber that can be extracted from the funds made avail- 
able to us. This means that we have the strongest interest in economy and 
efficiency so that the research dollar will be most productive, 

The task of creating an institution where research can be truly integrated 
and productive is extremely complex and difficult. Many of the problems are 
intangible, but nevertheless of central importance, 

A, Staff of Tcp Caliber 

Obtaining men of the highest quality is fundamental. Given a salary 
scale that is far below what industry can pay and particularly below the amounts 
that qualified clinicians can earn, we have done very well in attracting 
excellent scientists. In the two or three years ahead, we shall continue to 
fill in other key positions. Our recruitment is spread over about a six-year 
period not only because of the care we take in selecting people, but because 
we wish our hiring to cause the minimum disturbance to medical schools, 
hospitals and universities, 

B, Ensuring Collaboration 

Another matter of concern to us is to create the general expectation 
that collaborative work among Institutes and between clinicians and laboratory 
people is the normal way of life. Here we are working against fairly 



prevalent attitudes. The physician often feels that the scientist has no 
understanding of patient care and hence a subordinate role in clinical studies. 
The scientist in turn often believes that the physician has no appreciation of 
the ej^erimental method and hence is not a fully competent scientific colleague. 
We have to modify these attitudes to build the kinds of research teams we are 
aiming fore 

At the same time, we have to make sure that the individual who fvuictions 
best and has a great deal to contribute as an independent individual is given 
an adequate chance to produce, 

C, Hal nt aining ComTHTunic ati on 

In viewing the evolution of the National Institutes of Health towards 
our ideal, we see the maintenance of scientific communication— the easy exchange 
of ideas and facts— as critically important, Wfien people are expected to work 
with others xirhose fields ax^e relatively strange to them, there has to be a 
common meeting ground of understanding. Even within one scientific field, 
knowledge and ideas increase so rapidly that a scientist is hard put to it to 
keep up with his field. And if he does not keep up irdth his field, he begins 
to ■ a second-rater, lie feel almost a moral obligation to those who have chosen 
to throw their scientific careers in with us to provide the chance for growth. 
This is not a matter of personal satisfaction for scientists either, but a 
matter of setting the conditions which enable them to do their jobs well. 

An indispensable element of scientific communication is the ability to 
meet scientific colleagues. One of the differences between an in-bred, sterile 
research organization and one that is vigorous and productive is the range of 
contacts of the staff, !je feel that investment of a moderate part of our 



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appropriation in travel to scientific meetings pays for itself many times over. 
For the coming fiscal year, it is important that we have funds to allot to 
travel to scientific meetings in sufficient amounts so as to provide real 
implementation to the acquisition of the vital new views and information that 
are such an important stimulus to high quality research. 

D, Institute— Clinical Center Integ ration and Flexibility 

Another problem on which we continue to work is the integration of 
seven separate Institutes in a single building. This involves a delicate 
compromise between centralization of services that can be most economically 
and most effectively performed by a single Clinical Center organization, and 
retention in the Institutes of decisions-particularly on the research side- 
that must be left to the individual programs. This is an internal management 
problem that we are settling ourselves. 

In integrating research, flexibility-the ability to shift men and 
resources as the needs of specific investigations may indicate--is of key 
importance. Any impediment to our ability to push our resources quickly and 
easily into the areas of research where a stronger effort is needed will reduce 
the research return on the investment in N.I.H. It would, for example, be most 
difficult for us to conduct studies most effectively if our budget were 
arbitrarily divided into "clinical" and "laboratory" components and this 
compartmentalization were carried over into program operation. There is a 
good deal of work that is purely clinical or purely laboratory, but there is 
also the vital area-at the heart of the concept of the Clinical Center-where 
freedom to move in either direction is essential. We are most appreciative 
that the Congressional budget gives us this degree of freedom, and we intend to 
show by results that the action is wise. 



- 16 - 

In terms of general development of the research program at N.I.H., the 
budget provides for the activation of 350 beds by the end of fiscal year 19^$* 
We believe tlrnt the clinical care funds and the research funds to be so 
balanced in the budget that we can both take good care of this number of 
patients and build a sound research program around them. Of course, the 
welfare of the patients comes first, and we xjill always keep the number of 
patients within our capacity to provide the best medical care, 

II* Evolution of Clinical Research 

As the number of patients increases, each Institute will move pro- 
gressively to include a type of research where groups of patients with similar 
diagnoses and other characteristics are the basis for clinical studies. To 
date, a substantial portion of the clinical research has had to be on a series 
of individual patients. The group approach will not only speed investigations, 
but make them more effective. 

At the same time, specific clinical studies will become more detailed, 
complex and refined. During the current fiscal year, the depth of most studies 
was limited by operating problems associated vjith inaugurating patient care and 
by 'he fact that some key investigators had not yet been recruited, 

III, Prospective D evelopme nts in the Grant Program s 
A, Research Grants 

The medical research talent and facilities of the Nation are not yet 
receiving support at the optimum level from the scientific vievrpoint. The 
budget proposal for 1955 in the research grants field—a total of i?27,7 million- 
is not a proposal that will move the Nation forward to^^rard attainment of the 
optimum level. In this period of fiscal strain, the general economic effects 



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of Federal expenditures as well as research considerations must of course be 
taken into account in setting medical research grant levels, 

VJe all look forward to the day when heavy domestic and foreign defense 
ejcpenditures can diminish so that a greater share of the product of our 
economy can be devoted to health and other areas of productive effort. Mean- 
while, we can improve the program by paying careful attention to the way we 
handle the funds. 

Beginning in fiscal year 19$Sf we hope to make an administrative 
adjustment of minor importance in total budgetary terms, but of substantial 
iirportance to scientists and the institutions with which they are affiliated. 
This change is an increase from a maximxim of 8 percent to a maximum of 15 percent 
in the proportion of a research grant which will be allovjed for the indirect cost 
of research undertaken by grantees. It has become increasingly clear that the 
lower allowance now in effect falls far short of meeting the costs which schools 
must meet when one of their staff members receives a grant from us. The school 
has to provide utilities for the laboratory, expensive library service, housei*i 
keeping services, and so forth, that are not part of the direct costs of research. 
We believe that by increasing this allowance to 1^ percent, we will be dealing 
more equitably with the institutions. Even the increase to a maximum of 1$ 
percent will not fully cover all of the indirect costs in many institutions. 
But we continue to believe that a sharing of the costs of research, rather than 
a 100 percent Federal assumption of costs, is a sound policy, 

A new program in the field of chemotherapy of cancer will come into full 
flower during fiscal year 19^5. This new venture, initiated during the coming 
year, is a highly organized multiphasic approach, the primary target being the 



- 18 - 
lymphomas, more particularly leukemia. The program wi3-l bring the biologist, 
the organic chemist, the pharmacologist and the clinician together in an 
integrated program. Its progress will be guided by group direction within 
a framework that permits such rapid interchange of information as is usually 
not possible outside of a single organizational unit. The program was 
initiated in the belief that exploration of this particular field, in the 
particular manner and at this particular time will be highly rewarding.... 
perhaps as great as was the case in other fields of chemotherapy such as 
the malarias and bacterial diseases. 

B • Teaching and Training Grants 

In the manpower area — teaching grants, training grants, training 
stipends and research fellowships — the functions and objectives of the 
programs remain as they were in earlier years. The level of the programs 
will be reduced in 1955 about 10 percent below the 1954- level. As in the 
case of research grants, this represents not a reduction in need, but an 
adjustment to the realities of the Federal budget. 

We anticipate further strengthening of medical school curricula in the 
heart and cancer fields if the budget is adopted. 

We also can predict that about 90 percent of the research fellows will 
continue to remain in the medical research field. 

C . Grants to States for Control of Digease 

As the flow of research findings is augmented, the productivity of 
measures to control chronic disease in the States will increase. 

The grants to States administered by the Mental Health, Cancer and 



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- 19 - 

Heart Institutes, proposed at the sv5»7 million level appropriated in 19Shf will 
complement efforts in other fields that are administered by the Bureau of State 
Services, The Institute Directors are prepared to explain the variety of early 
detection and diagnosis techniques applicable to the specific disease groups, 

COMCIUSION 
We are pleased to be able to report accelerating progress in virtually all 
fields of medical research. 

This progress has come about not by chance, but as the result of joint 
pub lie -private support of medical scientists. This support has come at a time 
when a solid scientific justification for intensified effort is warranted. The 
support has been provided from both public and private sources in a way that has 
expanded rather than limited the ability of scientists to do what they consider 
most productive. Those of us whose life work is medical research, are truly 
appreciative of the understanding and support iirhich has always marked both the 
deliberations and the actions of this Committee, 

The Nation is now reaping dividends on its investment. With reasonable 
stability in support and ^^risdom in handling funds, we can look forward to 
continued progress < ' 



OPSNETG STATEMENT 

by 
Ernest Me Allen 
Chi.ef , Division of Research Grants 
National Institutes of Health 
Public Health Service 
before 
COMITTEE ON APPROFRIATIONS 
1956 ESTIMATE 
for 
"Operating Expenses^) National Institutes of Health (Division of Research Grants)" 

tlr. Chairman, and members of the Commttees 

The Division of Research Grants, National Institutes of 
Health, was established by the Surgeon General of the Public 
Health Service in 19U6 under Congressional authority included 
in the Public Health Service Act of 19hho The Division has two 
functions? one, to provide teclmical review and certain admini- 
strative services for all Public Health Service research grants 
and research felloiirahips; the other, to administer the general 
research grants program (identified in the Appropriations Bill 
as Operating Expenses, National Institutes of Health), 

Miile many major areas of medical and biological research are supported 
by the seven Institutes of the National Institutes of Health, highly important 
segments of the total research needs raiist still be supported from the general 
research grant funds. Although this program is not oriented towards groups of 
specific diseases, the research it supports will give rise to new knowledge 
which may well serve as the baseline for significant research acconrplishments 
in any one of the many categorical areas of research* 

Support for fundamental and clinical research not provided by the 
Institutes must be maintained and, as conditions and funds permit, expanded 
as a most effective means of asstiring advances in the total field of health. 
For 19$6 it is proposed to continue this program and to expand two programs 
of research that urgently demand special attention and emphasis. The first 
of these, water pollution, will require an additional |1, 000, 000 for research 
grants; the second, research on improved nvirse utilization, an additional 
$6253000, 



COWTBIUATIOM OF CURRENT ffiOGRM 

The special mission of the noncategorical program is to bring fimda- 
mental medical research to the point where application to a specific problem 
can be seen. Support for this type of research requires soroeiArhat more than 
half of the available funds ;, yet its importance is not readily understood. 
Even the highly- trained scientists who make such studies almost never 
appyeciate at the outset what the practical benefits may be. Nevertheless ^ 
progress in clinical medicine would soon cease if fundamental research were 
halted. 

Oftentimes the proposed fundamental research is recognized by an 
Institute as most appropriate for support. In many instances ^ however, the 
work is of such nature that it does not appear to be pertinent to the 
objectives of the Institute, or the proposed investigation may have such 
broad application that no single Institute has the particular interest 
needed to ensure support. Meritorious projects of this character will be 
supported from general research grant funds. A good example of the latter 
type is a grant recently made to a young professor of chemistry, considered 
a genius by many of his fellow scientists. This grant was paid from general 
research grant funds because his studies covered a variety of natiu'al products, 
including synthesis of quinine. On December 26, 195Uj the New York Times 
announced that this investigator had successfully synthesized strychnine and 
used this fact as the first of several reasons for concluding that 195U had 
been a "stimulating year in chemistry." 

The importance of fundamental research is best demonstrated after the 
practical applications are known. The value of arainopterin in prolonging 
the lives of children stiff ering from acute leukemia is well known to this 



- 3 - 

Committee, which has shoivn great interest in cancer chemotherapy. Historically, 
though, aminopterin grevf out of studios of the yellow pigment of butterfly 
■vvings and studies of the effect of sulfonamide drugs on the bacteria v/hich 
grow in the intestines of rats. Another recent medical milestone, also v;ell 
knovm, is the discovery that ACTH (adrenocorticotropic honnone) and cortisone 
remedy conditions which had previously resisted all kno\vn forms of treatnent, 
I know this Committee will be pleased to recall that prior to this discovery, 
a grant of $30,000 from the Division of Research Grants' funds stimulated 
the production of ACTH in sufficient amounts to keep research in this area 
alive. This early work, unrelated to any specific disease, laid indispensable 
ground work for the dramatic clinical findings v/hich came later. 

This program has continued to support fundamental studies of the 
pituitary hormones and only recently tvio nev; brealc-throughs have occurred. 
Scientists at the University of California have succeeded in isolating 
extremely concentrated preparations of growth hormone which in early tests 
have greatly increased the efficacy of ACTH in the treatment of malignancies. 
A quite different milestone was passed at Cornell University where a grantee 
succeeded in synthesizing another pituitary hormone, oxytocin, which for 
years has been widely used to aid childbirth and lactation. This is the 
first occasion in which man has manufactured in the test tube a biologically 
active protein-like substance. Knowledge of the chemical components of this 
substance vdll aid in fvirther study of the use and limitations of ojcytocin. 
More importantly, this discovery of a m.ethod for taking the amino acid 
building blocks and constructing a functional fragment of a protein brings 
us a stop nearer to the understanding of life. Itself and paves the way for 
future advances in the test tube synthesis of proteins Virhich heretofore could 
be manufactured only in the living body. 



- i; - 

In addition to these fundamental studies, the general research grants 
program of the Division of Research Grants supports a wide variety of research 
on clinical probleius, such as those represented by the follov:ing areas. 

Fetal and neon atal deaths . Over the past 50 years, scientific advances 
have resulted in a rpectacular reduction of infant mortality. The infant 
death rate has dropped from l62 per thousand in 1900 to 31.8 per thousand 
in 1950j but this means that over one hundred thousand babies still die each 
year. Furtherrrore, conservative estimates of stillborn children would run 
into the hundreds of thousands yearly. 

The causes and methods of prevention of some of these deaths are 
already known so that some improvement can be expected by wider application 
of existing knowledge. To a great extent tho causes in the majority of 
cases remain unknovm and methods of prevention must await further research. 
The general research grants program is supporting some v/ork in this area. 
For example, a cooperative study by investigators in different cities on 
the causes of sudden death of infants in apparently good health has uncovered 
the surprising fact that an intensely severe i-espiratory disease was often 
present in infants presumed to have died of mechanical suffocation. This 
research has not only posed a new research problem, but also contributed 
to the alleviation of the mental anguish of parents who might blame them- 
selves under the tragic circumstances. 

Diseases of the gastrointestinal tract . For the average family, the 
great burden of medical expense and the great toll of human suffering are 
tho result of diseases vrhich are not fatal. Many of these fall v/ithin the 
area of responsibility of the general research grants program. For examrale, 
diseases of the gastrointestinal tract are of coiviaon occurrence. It has 



been estimated by experts that one of these diseases, peptic ulcer, afflicts 
12 percent of all American adults at one time or another. In World War II, 
the Armed Forces excluded men iflith ulcer histories but, despite this pre- 
caution, more than 77,000 servicemen developed ulcers. Over u8,000 were 
separated from the service as a result of ulcer disabilities, adding greatly 
to the national economic burden through subsequent pensions. 

Some of the most important contributions to the treatment of peptic 
ulcer have been made by grantees of this program through application of 
knowledge gaiiied in basic studies. Tliree grantee surgeons at the University 
of Chicago, University of r4innesota, and the University of Washington, have 
developed a variety of new or combination operations designed to meet the 
different needs of individual patients. These include improved methods of 
cutting the nerves to the stomach, removal of the acid-secreting portion of 
the stomach, and several new ways of connecting the stomach to the intestine. 
The mortality from gastric surgery has been reduced, and many of the post- 
surgical complications have been eliminated. Other grantees are devoting 
their efforts to the development of better methods of drug therapy for the 
ulcer patient. 

Diseases of the reproductive tract . The diseases of the reproductive 
tract are numerous and varied. Iferor such diseases result in sterility, a 
condition which adds to the heartaches of childless couples. Research has 
already shown that some of the diseases and conditions causing sterility 
may be remedied or prevented, but much remains to be done, especially at 
the fundamental level. An example of the work supported by the general 
research grants program in this area is research at the University of 



- o - 

Pennsylvania concerned with the biocher.dcal changes taking place iir.tnediately 
follov/ing fertilization. 

Toxicology . The problems in toxicology become greater iivith every 
passing day. Thousands of new chemical compounds are being put to use in 
increasing amounts in drugs, food, cosmetics, houbehold supplies, and in 
agricultural and industrial chemicals. Unfortunately, many of these new 
compounds have been found to be toxic to manj the detrimental effects of 
others are not yet knovm. Some of our grantees are attacking segments of 
the problem. For example, at Utah State Agricultural College, studies are 
under way to determine the histological changes iri tissues of animals fed 
different insecticides. This is particularly inportant because of the wide- 
spread use of new insecticidal poisons v/hich are constantly coming onto the 
market. If it is demonstrated that harmful residues retrain in animal tissues 
vrhich are later consumed as food products by man, a definite public health 
hazard may develop. 

Diseases of the skin . Diseases of the skin receive amazingly little 
attention in view of their importance. Many severe dermatological conditions 
are caused by bacterial or fungal -infections and a tremendous amount of money 
has been expended in the preparation and use of superficial medicaments to 
counteract these disease manifestations. As a consequence, expert derma- 
tologists cite that nearly half their patients — estimated in the hundreds 
of thousands yearly — are those who seek relief from conditions caused by the 
unwarranted use of preparations purported to relieve itching, to cure bacterial 

or fungal infections, or to reduce inflammation of the human skin. Yet very 
little is known about the precise cellular mechanisms involved in sensitization 
of the skin induced by topical application of medicines vrhich are in widespread 



- 7 - 

use. Because of its thin structure, the skin is very difficult to study. 
Microtechniques have recently been developed, hovfever, which v;-ill at last 
permit controlled studies. If additional raanpovrer can be trained and new 
centers of skin investigation encouraged, there is good reason to hope for 
an accelerated rate of advance in this important area. 

Public health and preventive medici ne. Medical research tends to be 
oriented tovirard the specific disease and the management of the ill individual. 
Yet to achieve maximum improvements in the health of the Nation, methods must 
be developed to meet the problems of preventive medicine at the community 
level. This oftien calls for an entirely different approach and it is the 
responsibility of the Division of Research Grants ' program to support and 
stimulate research of this sort. From a research standpoint, many diffi- 
culties are presented because methods for community studies are largely 
undeveloped. Steps are being taken to overcome these difficulties in some 
areas j for example, in the noasurement of community morbidity. 

In California a grant-supported survey conducted by the State Depart- 
ment of Public Health has developed a household interview method which can 
accurately determine the extent of chronic illness in a limited area. This 
method is now being applied in a state-wide sampling survey which v/ill pro- 
vide California with information basic to the operation of its health program 
and other States with a technique vfhich can be applied elsewhere. 

The entire field of public health is undergoing revolutionary changes 
related to the shifting picture of illness in a community. Public Health 
personnel, trained primarily to control the epidemic diseases, arc confronted 
increasingly with community problems in the prevention of degenerative and 
chronic diseases afflicting the aging population. One of bhw great research 



- 8 - 

challenges today is the rapid deTelopment of means for translating kn.owledge 
of disease in the indi-vldual to methods of prevention at the comnitmitgr level. 

SPECIAL IRROBESM AREAS 

Increases are requested for two specific areas of research? additional 
work in water pollution (for which $1,000,000 is requested), and iraproved 
utilization of nurses (for which $62.'5jOOO is requested), Applicatior© for 
support of research in these two special fields must, as is true of all 
Pu-bli-c Health Service research grants, be recommended for approval by a 
statutory Council. 

Special research program on water pollution . An ample suppljr cf 
water of good and safe quality is essential to community health and well- 
being, especially to domestic living and to the industrial activity which 
is the basis for community livelihood. Great expansions in urban popula- 
tions and industries have steadily increased demands for water, and at 
the same time have greatly increased the discharge of waste materials to 
streams which fuj^nish our raw water supplies. With a continually expanding 
econon55r, it has become apparent, in more and more areas, that only by re- 
peated reuse of water can the anticipated future needs be met. This means 
that waste discharges— both from the home and from industry—must be treated 
to remove polluting materials before being discharged to streams. Thus, 
the water in the streams can be vsed over and over as it flows from city 
to city and from industry to industry. 



- 9 - 

Tho technical complexities of v;astc treatment are continually 
compounded not only by the increasing voluracs of scvragc and industrial 
T/astcs but also by nciv types of rrastc materials, particularly from tho 
mushrooming chemical industry. The manufacture of thousands of neiv 
synthetic chemicals is introducing into our v/atcrcourscs more and more 
Tfastc compounds v;hosc effects on aquatic life, on human beings, and on 
sewage and T;atcr treatment methods aro but slightly understood. Methods 
for removing these substances from irastcs or from streams have generally 
not been dovclopod and, moreover, methods arc not even yet available for 
detecting and collecting them for analysis and study# 

A review of tho research projects previously supported by the Public 
Health Service illustrates some of tho research attempts that arc being made 
and tho need for a much greater effort for solving those problems, Tho 
object of such research is to provide tho basic knowledge v/hich vail permit 
communities and industries to proceed, within their own financial resources, 
vath the design and construction of tho necessary v;aste treatment works» 

Scientists at sixteen institutions throughout the country aro engaged 
in research on sewage contamination and sewage disposal methods. Large 
amounts of scvragc and wastes are still discharged iiithout any or only 
superficial treatment into surface waters. Such an instance is the area 
of Biscaync Bay, Florida, Trficrc investigators have been carefully measuring 
tho deleterious effects of such discharge on the marine life and the degree 
to T/hich tho water is rendered unfit for human use* The design for the 
scv/ago plant nov/ contemplated for this area will incorporate features based 
on some of the findings developed under research grant projects at tho 
Massachusetts Institute of Technology, tho liiivcrsity of Colorado, and 
Purdue University^ 



- 10 - 

Another important problem area is that of modifying or improving the 
efficiency of existing methods of SGwagc treatment so that existing plants 
may be adapted to treat larger quantities of r/astes, or to remove ncvrcr types 
of materials which would be deleterious to dovmstream users, or to continue 
to function despite the prcscnco of specific -waste materials v/hich interfere 
vdth conventional treatment plant operations. The trickling filter method 
and the activated sludge method, for example, are being studied under 
research grants. 

Another type of research investigation shovdng real promise is that 
loading to the development of new and more economical methods of sewage 
and vrasto treatment, A research grant project at the University of 
California, for example, has developed fiindamcntal data on the related or 
symbiotic effects of algae and bacteria in the treatment of soTrago by ponding. 
Those data indicate that such ponds can be reduced in size and at the sane 
time operated under controlled conditions to produce a highly purified 
effluent and may oven be adapted to mass algal culturing to recover the 
valuable fixed nitrogen present in ^Tastes in the form of a highly nutritious 
animal food. 

Intensified research is needed also to study the viability and 
destruction of pathogenic bacteria and other harmful microorganisms \ihcn 
these pass through treatment plants, or arc discharged to streams or arc 
percolated into the ground, or when disposed of by irrigation, Yorkers of 
the Kansas State Board of Healthy for example, have shoivn that the histo- 
plasma fungus is not removed by the conventional flocculation and filtration 
procGsscs v;hich are the basis for most modem filter plant design. Also, 
the Nov; York State Department of Health has done v:ork loading to the 
dovolopmcnt of a now method for the quick nnd accurate identification of 
TiTascri in vratoro 



- 11 - 

The proposed research grants program in Virater pollution control, 
coupled mth the stimiilatory activities of the Taft Sanitary Engineering 
Center at Cincinnati, vdll periTiit the Public Health Service to provide the 
nucleii of new findings essential for mobilizing the national resources to 
a comprehensive approach to th6 serious and grov/ing problem of vrater 
pollution. 

Research on improved nuj?se utilization . Nursing service is essential 
for the conduct of modern medical programs both preventive and curative. 
It is well known that the demahds for nursing service exceed the present 
supply. It is not expected that this demand can be met through an increase 
in number of professional nurses. Ways must therefore be found to render 
more effective service vdth the present supply. 

Research into nursing and its management can develop new methods 
which will reduce the gap in seol'vices. For exaiAple, a recent research 
study involving both nurses and doctors experimented with different nursing 
methods. Certain ones v/ere found to be far superior to others in speeding 
patient recovery. A few studies like this and researches on management of 
nursing services have yielded proniising results, Hov/ever, only a beginning 
has been made. 

Nurses of today must keep pace vdth the dramatic advances in medicine. 
Modern nurses care for heart and brain surgery cases and must knov; care and 
rehabilitation techniques for the long term chronic patient. They must be 
able to predict and manage the behavior of the psychiktric patient. Nurses 
must be able to fit into team operatioh but also be able to act independently. 
Research is needed to develop improved methods of meeting patients' needs and 
to determine how nurses are to be prepared for their grovang responsibilities. 



- 12 - 

Practical nurses and nursing aides combine r/ith professional nurses 
in supplying nursing services needed in hospitals, yet only one-sixth of 
the practical nurses and a very small percentage of the nursing aides have 
had training for their duties. Studies are needed to determine the proper 
training of these groups so that they can liberate professional nurses for 
responsibilities requiring more complex skills and judgment. Studies are 
also needed on the most economical and best way of administering this 
diverse group of nursing personnel so that patients -will get safe care 
and hospital finances avill be conserved. 

Nurses in managerial and teaching positions everywhere are 
strategically placed to implement the findings of research. Training for 
these positions should provide knowledge and skill necessary for applying 
research results. Increasing the number of these trainees is another factor 
in the solution of the shortage problerA and the value of this factor will be 
enhanced by an active research program. 

All types of nursing research require nurses -vvho are trained in 
research techniques. Relatively few nurses now knovt those techniques. Con- 
centrated training in research can prepare a larger number of them to 
conduct needed studies* 

The problems of nursing urgently need study and research. The 
proposed program will enable universities and other institutions to under- 
take needed researches. Findings will alter nursing practice and vdll affect 
the comfort and recovery of millions of people in hospitals, clinics, and 
homes, 

SUMvIARY OF 19^6 PIANS 

In 1956 the Division of Research Grants' program vdll continue to 
support exploration of ideas in fundamental, clinical, and public health 



- 13 - 

areas, and rail devote particular efforts to stinulate added research in 
the selected fields. Special attention vdll bo given to the prcbla'ns of 
diseases of the skin, to studies of human embryology and early dcvolopmcnt, 
to the problems of vrater pollution, and to research directed tovrard 
provision of more adequate nursing services* 



OPENING STATEMENT 

Dr, Flqjrd S. Daft 
Director, National Institute of Arthritis and Metabolic Diseases 

National Institutes of Health 
Public H3alth Service 
Befoie 
COMMITTEE ON APPROPRIATIONS 
1956 ESTIMATE 
For 
"Arthritis and Metabolic Disease Activit:|es" 



Mr, Chairman and Members of the Committee; 



Historical Background 

Although the National Institute of Arthritis and Metabolic 
Diseases is one of the yoimgest of the National Institutes of 
Health, it is comprised in part of some of the oldest and most 
productive research laboratories in the Public Health Service. 
The Institute was es-^.ablished in 1950 under the provisions of 
Public Law 692, which alst directed that it absorb the program 
of the former Experimental Biology and Medicine Institute, It 
conducts a broad program of laboratory research and clinical 
investigations, and supports research and research training 
through grants and awards. 

The first direct appropriation for activities of the 
Arthritis and Metabolic Diseases Institute was in 1952, when 
nearly four million dollars were made 0,vailsl)lo<, Tii© 
Congress has continued to increase support of this program with 
each successive year — approximately four and one-half million 
dollars in 1953, seven million dollars in 195u, and more than 
eight million dollars in 1955* The Institute has now developed 
a well-rounded attack, both upon the broad spectrum of chronic 
diseases in thj.s area and upon basic laboratory studies related 
to these conditions. 



This is but the fourth time that the National Institute of Arthritis 
and Metabolic Diseases has been privileged to appear before this Committee 
and discuss its programs and its progress with you. 



'mmB<^ 



•"^^ 



~2- 

ihe relative youth of this Institute is not reflected in 
its internal structureo When we were formed by an Act of 
Congress in 19$0f it was our ;ood fortune to acquire a number 
of long~established laboratories whi/ah f or many years had been 
making distinguished contributions to medical science in such 
fields as nutrition;, pathology, pharmacology, chemistrj', and - . 
physical biology* Thus at the same time as the Institute 
acquired identity, it also acquired a souno. base of fundaraental 
studies upon which its program of clinical investigations could 
be builto 

Research interest in arthritis and the metabolic disorders 
is of comparatively recent origin..* In medical science, research 
interest usually is associated with research opportunity* It 
follovjs that the time must b, ripe for significant advances in 
this field* The accoiaplishiaents since the establishment of the 
Institute in 19^' demonstrate tht validity O- this hj^othesis* 

The groi'fth oi public and professional interest i.i ^thritis 

rheumatism, and related disorders has folla^jed an intersting pat- 
tern* In 19l;6, only abou':. O50>000 was spent in rheura::tic disease ' 
research) there were fei: scientists interested in the field, only 
a handfvl o_ artliritis clinics, and ■d.rtually no opportiinities for 
specialized research training* Th. n tMags began to happen with 
drai.iatic suddenness* In l^UJ, th-^ Arthritis aix! Rheumatism Foun- 
dation was established to suppor o research, public education^ and 
service* In 19U9, liench and Kendall o.. the ilayo Clinic made their 



revolutionary announcement of the effectiveness o2 cortisone and 
ACTH in suppressinc arthritis* In 19^0^ Ih^ .atical Institute of 
Arthritis and ..eta'.-'olic Diseases was created* These developments, 
both private and public^ set the sta£;e fo:-- prpgress* :lni there have 
bo^i more ac'vances in the last five years than bhere were i.i the 
preceding five hundred. 

Diseases with ii?ldch th» Institute is Concerned 

Heart disease, cancer, anc': mental illness arc O- covrse kncrwn to 
be families o, diseases, an no':, single disease entities in themselves* 
Tho members of the family become more numerous anc ;.he relationships 
more complex when one atte..'.pts .0 describe tho f\:ll range of diseases 
an disorders encompassed in the fields of interest O- the rational 
Institute of Artliritis anc . etal.'olic Diseases. Yet there is ample 
reason for groupinc: them to:;,-ther for a unified research effort, for 
they ha.e much in coi.imon* 

Ohv. major category 0.. diseases vdth which we are concerned can be 
called th^ rheumatic disorders* They a, e characterized by pain and 
stiffness in joints and muscles^ often res'-dting in swelling and 
inflammatioii Li th. affected areas» In the several forms of 
artliritis (rheumatoid artliritis, osteoartliritis, and gout)j tlae joints 
themselves are affected* '.vhen the rheumatic disease is located in the 
connective tissue^ particularly around joints, muscles, and tendons 
(as in fibrositis, bursitis, neuralgia, lumbago, or sciatica), it is 
called non-articular rheuinatism* A tl ird group of rheumatic disorders 



"Vrt .^r 



h 

is called the collagen jdigeaseSjj i^ which the c^nnectivs tissue is 
attacked, inflamed, and e.' ■ a destroj'-ed. These diseases bear esSterio 
names -- lupus erythematosus, scler'^derma, polyarteritis nodosa, 
deriTiatomyositis t— but they ar^ serious and often fatal disorders. 
The second major category of diseases to which this Institute 
gives special attention are the metabolic disorders. In this family 
of diseases, the similarity is in the defect cr deficiency in the 
complex biochemical processes by which the body "metabolizes" f-^od, 
air, and water, converting them, into the growth and energy which 
maintain body structure and function. The research problem here 
has to do essentially x-jith hormones, enzymes, and vitarains — the 
great classes of corapoui'ids invnlved in the control of m^etabolism in 
the body. Diabetes is perhaps the most inportant of the metabolic 
diseases; and the defect there, for example, is the inability of the 
body to utilize sugar properly because of the absence rr improper 
f'inctioning of a hormone of the pancreas called insulin. Other diseases 
in this group are cirrhosis of the liver, peptic ulcer, the anemias, 
•steoporosis, and other conditions, Anpther kind of metabolic disorder 
results from deficiencies or excesses in diet — either primary deficiencies, 
faulty absorption of nutrients, poor utilization of nutrients, or special 
dietary needs resulting from disease, trauma, surgery, or other stress. 
Included in this group are deficiency diseases such as beri beri and 
pellagra^ mineral deficiencies such as secondary anem.ia and goiter, stunted 
growth in children; pernicious anemia, sprue and the inegaloblastic aj^emias 



5 



of Infancy =aiid pregnancy j' and obesity— perhaps the nost important number ' * 
of this gtovp becaiise of its relation to such diseases as diabetes, »"'« •' 

arthritis, heart disease, and certain forms of cancer. 

Thus the areas of research interest T:ith -ijhich the National Institute 

of Arthritis and Iletabolic iJiseases is directly concerned impinge on 
virtually everj'" disease of :vian. It is of particular value, then, for this 
Institute to be set in a total research environ:ient which encourages a 
maximum amount of interplay between its scientists and those of the other 
six Institutes, 

'The Human and jiicononic Burden 

Since the diseases related to the tfork of the National Institute o£ 
Arthritis and Iletabolic Diseases are so diverse, consisting largely of 
conditions which are more incapacitating than fatal, it is difficult to 
get an accurate assessment of their current status as health factors 
among the American population. Our best estiiriate is that roughly 2Sp 
of the people are directly affected. The economic burden has been 
estimated to ar^proach one billion dollars a year. 

lie can be more spejcif ic, however, in assessing some of the major 
disease entities, '% Icno': that arthritis and the related rheuraatic 
disorders cripple and incapacitate more people than ary other chronic 
illness in this country. Today, more than ten million suffer the painful 
torments of these conditions. Of these ten million, approxii'.iately one ... 
million are perr.ianently disabled, unable to earn a living and thus a 



-iCr.. 



.\'i. 



i 

hea"vy economic burden upon their families, their communities, and the 
Nation as a whole, Rheianatoid arthritis, the ^nost vicious of the 
rheujnatic diseases, is knoim as the great crippler; it is responsible 
for the disability and economic loss among people in their most pro- 
ductive years* 

I'Je knox-r that about 2^,000 people die each year from diabetes, and 
that 25>000 more die of complications brought on by the disease. Approx- 
imately two million people in the United States are afflicted with 
diabetes J nearly half of these have the disease in a relatively mild 
form, and the symptoms go unrecognized, tut diabetes has an insidious 
and alanning way of creeping up on its vic;:feiras and catching them 
unaware. Diabetes is hereditary, and diahetics are livinr longer 
because of insulin, so the disease continues to increase in incidence* 

Statistics of this kind are staggering and somewhat depressing. 
The hope for progress lies in a many-faceted orogram that extends across 
the full range of research, training, medical -.iractice, and pu.hlic 
education. The Federal Government's part in such a program is centered 
in the '"ublic Health Service, X'Tith certain control and education 
functions vested in the Bureau of State Services, and Tiith research and 
training as the primary interests of the National Institute of Arthritis 
and Metabolic Diseases, 

The last four years have seen the Institute grow in size, broaden 
in scope, improve in coonerative relationships, and increase in scien* 
tific productivity, ■ e have been unusually fortunate in securing out- 
standing professional staff in key positions throughout the Institute as 
our program has extended into new areas. 



I would like to cite particularly Dr. DeWitt Stetten, who left The 
Public Health Research Institute of the City of Mew York, Inc. to become 
Scientific Director of the Institute, Dr. Stetten is internationally 
known for his research contributions, particularly in the fields of 
diabetes and metabolism. Our Clinical Director is Dr. Joseph J, Bunim 
widely recognized for his talented and perceptive applications of 
fundamental knowledge to clinical investigations in the rheumatic and 
metabolic fields. 

This Committee, which has played such an active role in the estab- 
lishment and support of our Institute, will be interested in some of the 
acconplishments of the past few years, I am pleased to have this 
opportunity to report back to you that significant progress is being 
made, both in our direct research operations at Bethesda and under the 
extensive program of research projects supported by grants from the 
Institute, 

Progress Against Rheumatic Disease 

One of the most significant and exciting medical discoveries of 1951; 
was announced in November by clinical investigators of the Institute at 
a scientific meeting of the American Rheumatism Association held at the 
National Institutes of Health Clinical Center, 

Two new drugs, metacortandralone and metacortandracin, had been 
tested in Clinical Center patients with rheumatoid arthritis, and were 
reported to be more effective than any other drugs known, including 
cortisone and hydrocortisone. The nex^^ conpounds, developed by a 
pharmaceutical house, had previously been tried only on animals. 



8 

Metacortandralone was tested in a series of seven carefully- 
selected patients ~ six women and one man, ranging in age from 16 to 
67 years. The duration of the arthritis in these people ranged from 
2|- to 2$ years. Prior to this trial, three of the patients had been 
treated only with aspirin, while the other four had received just about 
every type of recognized treatment, including cortisone, hydrocortisone, 
corticotropin (ACTH), phenylbutazone, and gold conqjounds. In no case 
had previous treatment produced adeqxxate response, and in three there 
had been serious, objectionable side-effects. 

The response of these patients to the new treatment was prorpt, 
positive, and consistent. Each improved rapidly, both objectively and 
subjectively. The second of the drugs, metacortandracin, produced 
equally good results in another series of patients. 

It is highly significant that neither of the nevr drugs, though 
four times as potent as cortisone, produced in any commensurate degree 
the undesirable side-effects so often associated with cortisone, 
hydrocortisone, and corticotropin. 

Neither of these new drugs can be regarded as a cure for arthritis. 
Although they provide what now seems a much more effective and safer 
therapy than any previously known, only long-term use will tell the 
final tale. Other medical research institutions, since our original 
announcement, have been subjecting the drugs to additional trials, and 
our own clinical investigations are continuing. Results to date confirm 
our original conclusions. 



other Advances. Not only have advances been made in the treatment 
of arthritis, but also in our I'nox-rled^e of the associated aneiuia, the 
activity of steroid hormones in the body, and other areas basio to our 
understanding of the rheumatic diseases. 

Many patients with rheumatoid arthritis have an associated anemia 
which is resistant to the usual methods of treatment. Radioactive 
isotopes, used to tag red blood cells of patients, have enabled Institute 
scientists to make important determinations concerning this condition. 
It has been found to result from an increase in red cell destruction 
plus a failure of the bone marrow to produce sufficient red cells to 
compensate. These findings should lead to measures for more successful 
treatment, increasing the resistance and stardina of artliritis patients. 

In another study small amounts of radioactive cortisone and 
hydrocortisone have been administered to animals and human subjects 
so that the body's distribution and disposal of these hormones could 
be accuratelj'" determined. Information has been obtained that will 
help us understand how these drugs act in rheiimatoid arthritis and 
related diseases. 

Institute investigators have found also that growth hormone and 
thyroid hormone profoundly affect the production of collagen, an 
important constituent of connective tissue, which in turn composes the 
supporting structure of the body. Since abnormalities of the 
connective tissue are known to occur in rheumatic diseases, this 
finding has an interesting relation to the arthritis problem. 



10 

A significant development at the Medical Colle're of Alabama, 
3irrain';tham, by scientists supported through an Institute grant, is a 
new teclinique by which they can obtain adequate quantities of normal 
Icnee joint fluid to enable them to make tests and coiiparisons. In the 
course of this study, a substance has been found in normal knee joint 
fluid which is not present in fluids from abnormal joints — a protein 
fraction. The study is continuing in an effort to find out why this 
fraction disappears when the joint is diseased, uhat happens to "it,, 
and when and wliy. The results may well answer many questions concerning 
possible causes of rheumatic disease. 

Progress Against Metabolic Dis_eases 

Less spectacular but significant progress has been made in the 
field of diabetes. Although the cause of diabetes is far from 
comiDletely understood, heredity is kno^m to play a role in predisposing 
individuals to the disease, and obesitj'" is a major factor in its 
development. 

Another important aspect of diabetes is the multiplicity of 
disorders that accompany it, such as arteriosclerosis, Tliis seems to 
develop prematurely in the diabetic population. Other frequent 
con^xlications are gangrene of the extremities, which leads to 
amputations; disease of the smaller blood vessels, particularly in 
the retina, which leads to blindness; and kidney disease, leading to 
failure of this organ. Long-term studies with a view to better under- 
standing and control of these serious complications are continuing 
under our grant program. 



11 

The action of insulin must also be understood in order to make 
better pro-^ress a'^ainst diabetes* Important studies in this area are 
under way at the University of Pennsylvania and the University of 
Chicago, both supported by .grants from this Institute, Significant 
progress is being made, Attacliment of the hormone, insulin, to body 
tisr;ues has been demonstrated, and the activity of the attached hormone 
has been measured. It has also been demonstrated that insulin affects 
the ease with which sugar crosses cell membranes. Both of these 
discoveries aid in luiderstanding the role of insulin in the body. 

In the course of chemical and biological studies of insulin, a 
contaiTiinant was encountered that has since been shown to arise in cells 
intimately associated td.th those that produce insulin itself. This 
substance, glucagon, is itself active in the regulation of sugar 
metabolism, although chemically unrelated to insulin. It appears to 
provoke a rise in blood sugar at the escpense of the sugar reserve, 
glycogen, of the liver. The role of glucagon in diabetes, and 
especially in the vascular complications of diabetes, is a subject of 
study by Institute grantees. 

The demonstration of insulin antagonists in the blood of some 
diabetic patients lias stimulated studies of the chemical nature and 
origin of such agents. Little is knox-m of these substances at present, 
but numerous suggestive leads are being follot^fed. Since the antagonists 
are causative agents of clinical diabetes, it is obviously imjoortant to 
learn as much about them as possible. 



12 

Other Metabolic Diseases . It was mentioned last year that studies 
are under way at the University of Utah on inherited metabolic defects 
leading to imbecility in infants. These are long-term studies that will 
require many years, but another important advance has been made in our 
understanding of the abnormalities of protein metabolism that accompany 
or underlie this group of diseases. It now appears that two amino 
acids, so-called building blocks of protein, are not metabolized 
normally in infants with this metabolic disorder. The amino acids 
involved are phenylalanine and tryptophan. 

In our endeavor to understand and combat metabolic diseases, we 
must advance our knowledge of the basic chemistry of the body. For 
example, we must determine the steps by which food materials are broken 
down and rebuilt into needed substances. This information must be 
gathered first from normal animals and subjects, and must then be 
compared with analogous information from animals and patients with 
metabolic abnormalities. 

It was long thought, for exanple, that sugars are broken down in 
the body in one way only, A major advance in recent years has been the 
discovery, principally by investigators at the National Institute of 
Arthritis and Metabolic Diseases, of a second pathway of glucose 
metabolism. Interestingly enough, the process appears to involve some 
chemical reactions which are the reverse of those occurring in photo- 
synthesis. 

Another major advance, by scientists of the Institute and other 
research centers, is the discovery of steps in the synthesis of 



9V/ 



13 

mucopolysaccharides. Abnormalities in this group of compounds appear 
to be basic to arthritis and other rheumatic diseases. Enzyme systems 
involving a newly discovered substance, uridine triphosphate, have 
been delineated, and some of the synthetic steps by which the body 
builds constituents of normal mucopolysaccharides have been precisely 
defined. 

Still another promising field of basic research in metabolism 
relates to nucleic acids, essential components of the genes. This 
research area is therefore fundamental to our understanding of all 
hereditary metabolic disorders. During the past year, and a few years 
preceding, notable discoveries have been made in this field both at 
the Institute and elsewhere. As a result, we are on the road to 
understanding the chemistry of the nucleic acids and the metabolic 
processes by which they are formed in the body. 

It is with real pride that we report the advances in fundamental 
knowledge resulting from these fundamental studies. They have no 
immediate application in clinical medicine, but they constitute the 
firm foundation upon which the seemingly spectacular clinical 
advances of tomorrow will be based. 

Significant Program Developments 

As previously stated, one of the Institute's major efforts during 
the past fiscal year has been the clinical study of two new drugs, 
most promising against rheumatoid arthritis. These drugs must now be 
evaluated in related rheumatic diseases. Moreover, the demonstration 
that steroids superior to cortisone and hydrooortison&' can be 



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11; 

prepared indicates that many other new conpounds will become available, 
¥e hope to continue the clinical testing of such compounds. At the 
same time our fundamental studies in the field of rheumatic diseases 
will be continued. 

A part of the increase in the 1955 appropriation for research in 
our laboratories was utilized to augment studies on diabetes and related 
metabolic disorders. Laboratory and clinical studies of hormonal and 
nutritional factors, and the relation of metabolic mechanisms to the 
clinical state, have been inaugurated, and new and expanded studies are 
planned for this year, A new clinical branch on diabetes and endocrinology 
has been organized and is being further staffed. 

Effective use has been made of the funds appropriated by Congress 
for research grants in fiscal year 1955. The support of promising research 
projects in diabetes and other metabolic disorders has increased 
substantially. During the coming fiscal year, we plan to assist ad- 
ditional worthwhile projects in this area, and to support to the fullest 
possible extent the clinical testing of new drugs in arthritis. Standing 
as we do at the threshold of major clinical victories against arthritis 
and related rheumatic diseases, it is inperative that forthcoming drugs 
be evaluated as rapidly as possible. 

A new program under way is designed to solve some of the problems 
of postgraduate training in arthritis, diabetes, and other metabolic 
disorders. Specialists in arthritis have long recognized a desperate 
need for the training of additional medical personnel in this area. 



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15 

There are only 800 to 900 qualified physicians particiilarly interested 
in the treatment of this disease, as attested by their membership in 
the American Rheumatism Association. Needed almost as urgently is 
postgraduate training in diabetes and other metabolic disorders. In 
recognition of the seriousness of this situation, a portion of our 
traineeship funds is being used to make a small start in a program of 
training grants to institutions. The response to the announcement of 
this program has been enthusiastic and speaks strongly of the needs in 
this area. 

The American Rheumatism Association held its First Interim Session 
at the National Institutes of Health in November, 195ii« This was in 
addition to the Association's regular annual meeting, and was 
necessitated by the much increased interest in this important field. 
The meeting was highly successful, and arrangements have been completed 
for a Second Interim Session at the National Institutes of Health in 
the fall of 19?5, This is only one of many ways in which the National 
Institute of Arthritis and Metabolic Diseases is working with appropriate 
professional and voluntary organizations to further research training 
and the clinical application of new knowledge in arthritis, diabetes, 
and other metabolic disorders. 

Conclusion 

There has never been better justification for intensified effort in 
research on the rheumatic and metabolic diseases. 



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16 

During the past year, with the discovery of the remarkable effective- 
ness of two new steroids in arthritis, another milestone has been es- 
tablished in the march of medicine toward the control and cure of a major 
chronic disease. 

This breakthrough opens new vistas looking toward success in this 
field. The new steroids point the way, and we can look forward confidently 
to even better antirheumatic agents in the near future. 

Today we stand upon a rapidly broadening base of fundamental 
knowledge, with major roadmarks established. We are convinced that 
the path of research in the rheumatic and metabolic diseases was never 
as brilliantly lighted, and that the time has come when intensified 
research effort will pay off with major gains. 



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OPENING STATE^iSl\rT 

Dr. John B.. Heller, Jr. 
Director, Na.tional C^ncer Institute 
Pal3lic Health Service 
"before 
COMMITTEE OK APPHOPRIATIONS 
1956 ESTIpIATE 
for 
Salaries, Expenses, and Grants, National Cancer Institute 



Mr. Chairuan and Meuters of the Cor.uiittee; 

The National Cancer Institute was established "by Act of 
Congress of Au^st 5» 1937 > for the purpose of achieving 
control of cancer in rnan throxu^i studios relating to the 
cause, diagnosis, and treatnent of neoplastic diseases, and "by 
supporting useful application of the results of such studies. 

Although cancer research has expanded nost rapidly 
since the end of World War II, the Public Health Service has 
been active in the field since 1922. At that tiuo cancer 
research within the Public Health Service was initiated by 
two groups of scientists - one at Harvard University and the 
other at the Hygienic Laboratory in Washington. These groups 
were nerged to form the nucleus of the N ^tional Cancer 
Institute. Under authority of the organic act of 1937. the 
chief provisions of v/hich wqro incorporated in Public La-w ^+10, 
the work of the Institute is divided into two broad areas of 
activity - tho acquisition of knowledge about cancer, and the 
dissenination and application of such knowledge. In the first 
area, the Institute conducts original research, both b.sic and 
clinical, in its ov/n laboratories; supports research by 
individuals in other institutions and organizations through 
grants-in-aid; and helps enlarge the supuly of q.ua.lified 
research investigators by awarding follov;ships to promising 
young scientists. To secure the widest possible dissenination and 
application of cancor knowledge so a,cquired, the Institute provides 
for grants, consultations, and denonst rat ions within the States; 
provides teaching grants to approved professional schools of 
nedicine, dentistry, and osteopathy; awards tra,ineoships to young 
clinicians; and distributes professional ?.nd lay educational and 
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National statistics suggest that on this very day approximately 650 
people will die from cancer. The cancer death toll is rising. Because 
I know we all share great concern over this situation, I consider it hoth 
a pleasure and an opportunity to discuss with you not only the programs 
and problems involved in the government's fight against cancer, tut also some 
of the strategic gains made in this struggle. Progress from year to year 
in this field of medical research is relatively slow, and the gains that 
are made are seldom spectacular, Taut I can assure you that accomplishments 
of very real value have "been achieved, not only in the lahoratory but also 
in the area of direct control of this disease in the population. 

EXTENT 01 CANCER 

I should like again to refer to the extent of the cancer problem on 
the basis of our latest statistical information. Cancer is unquestionably 
a major public health problem. In 1955 about 235iOOO persons will die of 
cancer. A-bout three quarters of a million will be under treatment, of v/hom 
550,000 will represent newly diagnosed cases. If prevailing incidence rates 
contintie, some 1,000,000 persons v;ill be receivinf.^ treatment annually for 
cancer by 1975. Why? Primarily because half of all cancer patients are 
between 50 and 70 years of age, and 'iur population is growing older. 
Unless the cancer death rate for older people can be cut drastically, the 
number of persons affected by this disease will increase by 50 percent 
in the next 25 years. 

Another factor must be considered. Ca,nccr is the second leading 
cause of death in the formative years of life, between 5 and l4. The 
postwar baby boom has sent the birth rate up steadily, thereby enlarging 
this age group in the cancer picture. 



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The economic loss due to cancer is staggering on two counts: the 
drain on the family's financial resources is tremendous over a long 
period; and millions of man~hours of work are lost, involving many more 
millions of dollars? worth of product and skills. Snail wondor, thon, 
that cancer is described as a "catastrophic" illness. 

With the Committee's permission I will discuss the future plans 
and needs of the National Cancer Institute in the light of some of the 
major accomplishments under our program during the past year* 

EBSEAEOE 

The ultimate goal of cancer research is to discover the hasic nature 
of cancer in man in order to esta.hlish means of preventing and curing ito 
Eut cancer is no simple disease which alv/ays exhibits the same symptoms. 
There may "be as many different kinds of cancer as there are parts of the 
"body where cancer may occur. The disease is not always recognizable for 
what it is until late stages of development. Symptoms vary among types and 
locations in the tody. As of this date, medical science knows of no one 
basic cause or cure of cancer. 

This variability of laalignancy is what makes cancer research imiq.ue. 
Cancer is a disease of the cell. Medical science is working at the lock 
to the cell with increasing expertness, and when the key is found which 
opens it and discloses the nature of the mystery , we may be very close to 
full knowledge of the fundamentals of life. Major research eraphasis at 
present is placed on basic questions concerned with the chemistry and biology 
of growth itself, because it is believed thiit increased knowledge of growth 
phenomena can load to more rational approaches to the cancer problem than 
is now possible. 



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A large part of our research program seeks to extend knowledge of 
the causes of the large group of related diseases included in the term 
"cancer," the nature of the transformation of cells from normal to cancerous, 
and the iDiological and "biochemical differences "between cancerous and normal 
cells which may "be exploited for therapeutic purposes* 

Cancer research is not without its successes, though we have jrot to 
reach "paydirt" In terms of the causes of cancer. Radiation techniques and 
instrximents tmknown ten and fifteen years ago are conmonplace today ~ and 
are snatching cancer sufferers frop death. Chemicals of un"believable 
complexity are serving magnificently as palliatives ~ and are easing pain, 
increasing the effectiveness of surgery, and prolonging life. Hew 
diagnostic tests now on trial are discovering cancer of the uterus in the 
earliest stages - and giving long life and extended motherhood to many women. 

Epdlemiology 

Knowledge of the nature and extent of cancer as a disease in the 
population is essential to a general plan of attack on the pro"blem involving 
la'boratory research and direct control measures. Data on prevalence, 
incidence, distri"bution, and mortality from cancer in human populations, and 
estimates of the influences of such factors as geography, environment, and 
race, are o"btained through epidemiological studies. In this field the 
National Cancer Institute has completed the total ta"bulation of data 
gathered in its studies of cancer illness in ten metropolitan areas which 
were initially surveyed in 1937-39 and rosurveyod in 1948-'4-9» This project 
is considered "by research authorities throughout the world as the most 
comprehensive of its kind ever conducted. Certain hypotheses as to the 
extent and nature of cancer have "been corro'borated and distur"bing trends 
disclosed. 



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Among the significant findings produced by this study are; (1) that 
the cancer death rate in the Nation's white population is definitely higher 
for men than for women, constituting a reversal of the relationship which 
had existed until recent years; (2) that the chance of developing cancer is 
a"bout one-third greater for white persons living in the South and the West 
than for those living in the Northj and (3) that there has "been a sharp 
increase in lung cancer generally; and (^) that lung cancer is to be found 
four times as frequently among men as among women-. 

In cooperation with the Veterans Administration, some 3C0,C00 World 
War I veterans holding government life insurance are being asked to fill 
out a detailed questionnaire which includes information on their smoking 
habits « Response has been dramatic. Replies have been received from over 
200,000 so far, and the data are being processed. It should be possible 
thereby to calculate more reliable rates of the incidence and mortality 
from lung cancer among smokers and nonsmokers than are now available-. 

The American Cancer Society is also greatly interested in this 
problem, and is conducting a S-year study of the smoking habits of 200,000 
men over 50 years of age to establish a connection, if any, between smoking 
and lung cancer. Information on the cause of death in the 5»000 deaths 
expected each year in the group is being recorded^ 

En vironmental-Occu pat ional Cancer 

Certain questions logically suggest themselves in the light of 
information about why people of different types, living in different localities 
or under different conditions, get cancer e 

A number of substances or compounds are known to bo carcinogenic oi* 
cancer-causing. Most of them are found in industry - some tars, certain 
petroleum products, radioactive materials, some chemicals involved in metal 



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- 6 - 

snelting processes, and other products of industrial activity. Froa such, 
findings it has "been possible to prevent harcif-ul exposure of the industrial 
worker in the handling of these materials. 

The Institute is vigorously pursuing a series of investigations in 
environnental and occupational cancer. 

Anong aany netals examined and analyzed in the laboratory, nickel 
and possibly chroniun have "been found to he carcinogenic. It is possible 
that in these cases the cancer-causing nechanism nay he related to reactions 
between "body proteins and such notallic dust when inhaled. It has also "been 
ahown this past year that certain oils used as petroleun substitutes (such 
as shale oil) possess some cancer-prodticing products. At the sane tine 
extensive studies of air pollutants are being made to determine their role 
in causing lung cancer. 

A general health survey is under way of workers esqposed to radiation 
and other hazards in the new uranium mining industry of the Colorado 
plateau. These miners are exposed to radioactivity present in the sineral 
dust. Study is being made of the effects of such contact and inl'.alation, 
and the type and incidence of cancers that develop. 

The Institute is also engaged in the study of the carcinogenic or 
cancer-causing potential of tobacco. In one project, the purpose was to 
determine the frequency of respiratory cancer among workers engaged in 
the processing and handling of tobacco materials in the manufacture of 
cigarettes. A major finding of this study was the close approximation of 
cancer mortality among these workers with that of the total population of 
the two States involved. 

Siochemistry 

There is no more important field in cancer research than that of 



- 7 - 

■biochemistry, which is concerned with the deternination of differences in 
the chemistry and netatolisn of normal and cancer cells. Basic research 
is teing performed on proteins, which are essential to life and on peptides 
and amino acids, v/hich are important components of protein. Particular 
attention is given to enzymes, which are proteins that selectively control 
most of life's processes. Another area of investigation is that of 
carcinogenesis, or the study of what causes norma.1 cells to hecome cancerous. 
A third area deals with hormonal influences or carhohydrate metabolism. 

The reported increase of peptides in the "blood of cancer patients 
suggests that more information on these very complex substances ia desirable. 
To this end National Oancer Institute biochemists have been active in the 
identification, synthesis, purification, and analysis of peptides. 

Proteins have been subject to intensive study, in view of their 
strategic role in living matter, and have been extracted from normal tissues, 
from tissues of tmaor-bearing animals, and from tumors themselves. New and 
more effective procedures have been developed for distinguishing and 
identifying various proteins and enzymes. 

Biology 

Although it cannot be said that cancer is a disease that is inherited, 
the probability that an individual may develop cancer is influenced by 
heritable traits, dietary factors, and hormonal stimulation. The heritable 
traits are a result of the action of the genes found in the cell chromosomes. 
The observation that the development of lung tumors in mice is associated 
with natural obesity has led to a study of the biological and biochemical 
mechanisms by which obesity is produced. A definite linkage between 
susceptibility to lung tiinors and a particular gene identified with 
obesity has been established, and studies are continuing on the correlation 



- 8 - 

totween inherited characteristics and the susceptibility to cancer. 

Experiment s are also under way involving the role of filterable 
agents, presunalily viruses, in the causation of cancers not previously 
associated with viral action. 

A study involving nice indicates that the incomplete renoval of 
large tunors night extend the life span. This suggests that even partial 
renoval of "inoperable tunors" night te of "benefit to sone hur.ian patients* 

Endocrinology 

A good deal of public interest has been nanifested lately in the 
subject of the effect of hornones on the body. Much of this stens, 
undoubtedly, fron a ntinber of interesting research disclosures. For example, 
our own work in this field has produced striking regression in breast cancer 
by the application of massive doses of female sex hornone» Similar 
injoctions have caused noticeable improvement in prostate cancer patients. 

One particular female sex hormone, progesterone, seens potentially 
useful in causing shrinkage of advanced breast and prostate cancer, but 
was found ineffective when taken orally. The Institute, therefore, is 
studying in animal tests a number of compounds rel".ted to progesterone 
with a view to finding more effective substances. 

The adrenal glands produce hornones which stimulate the growth of 
breast cancer, and in advanced cases these glands are renoved surgically. 
Animal studies have led to the development of a drUfg known as anphenone, 
which inhibits the function of the adrenal glands. Further experiment 
nay lead to the possibility of using anphenone to suppress this glandular 
function in hunans without resorting to surgery. 

An unusual characteristic of ttunors originating in hornone-producing 
organs is the excessive production of hornone by the tunor as compared with 



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- 9 - 

the nornal parent tissue. Many atnornalities result there^by in the "body. 
To iuprove the nanagenont of such tuners, our scientists are devoting 
considora'ble tine to improving nethods of detecting and measuring these 
harmful hormonal effects in the "blood and urine by chcnical and biological 
means • 

Since castration causes remarkable shrinkage of breast and prostatic 
tumors, sttidy is under way of the processes whereby these organs shrink 
when deprived of nornal hormonal support by the rem.oval of ovaries and 
testes. Present experiments with animals include starvation and special 
diets and escposure to heat and cold. 

The pituitary gland, located at the base of the 'brain, produces 
several hormones that control body growth and the functions of certain other 
glands. A nearby organ in the brain is the hypothalamus, which, when 
destroyed in animals, affects the pituitary gland and, in turn, the normal 
activity of those glands controlled by the pituitary. Those relationships 
nay have considerable importance in tumor control. Further investigation 
will attempt to define and clarify the manner in which the brain and 
pituitary gland cooperate in normal and abnormal growth processes. 

Chonical pharm.acology 

Research pharmacologists of the National Cancer Institute are isolating 
natural substances and synthesizing new substances which may either induce 
or inhibit the growth of cancer. Tests have been developed for determining 
the nature and effect of these compounds, their purity, and their lethality. 
So far, more than 500 drugs have teen identified as having cancer-destroying 
properties. 

The laboratory scientists have succeeded in creating by synthesis 
several typos of new chemical compounds with potency in affecting cancer 



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in aninals. They have also isolated sone naturally occurring agents from 
a considera'ble number of tissues of aninals. Further study on tho nechanisn 
of action of tuinor-affecting drugs has been successfully continued. 

Close collahoration between laboratory investigators and their 
clinical colleagues has been the rule v/ith regard to anir.ial expo rir.ientat ion 
with drugs desired by physicians for clinical trial. This situation obtains 
particularly in the preparation and adnini strati on of selected drugs to 
cancer patients in the Clinical Center. 

Other research done by this laboratory will be discussed a little 
later under "chemotherapy." 



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- 11 - 

Field Inve stigations 

In the attempt to control cancer with the knowledge at oiir disposal, 
the crux of the problem is to shorten the intervals betv/een onset of the 
disease and diagnosis, and "between diagnosis and the start of treatment. 
Prevention, of course, is of foremost importance as in any disease prohlem, 
tVii in fighting cancer the "best weapons are early suspicion, accurate 
diagnosis, and effective treatment. 

Methods of improving hoth the diagnosis and treatment of cancer 
are developed through field demonstration projects, usually in cooperation 
with state and local health agencies, and medical and research organizations 
and institutions^ One such project has demonstrated the practical useful- 
ness of a mass screening procedure which promises to "bring a"bout virtually 
complete control of the second most prevalent form of cancer in women. 

Next to "breast cancer, women suffer most from cancer of the uterus or 
wom"b. The cure rate of uterine cancer if caught in the earliest stages is 
95^ - lOC^ as against only 5/o when found in the advanced stages. Unfor- 
tunately, 3 O"*!* of k women are first seen and diagnosed in the advanced 
stages. 

In an attempt to develop a test or technique of some kind that would 
reveal cancer of the uterus in its earliest manifestations, the National 
Cancer Institute undertook two years ago to check thousands of women for 
uterine cancer "by means of a cell-examination test. The Memphis-She I'by 
County area, in Tennessee, was selected, and what is known as a cytology 
screening project was set up, with the cooperation of the local health 
department, the covin ty medical society, voliintary agencies, and the medical 
school of the University of Tennessee. This test is simple to perform, 
is not painful to the patient, requires no expensive equipment. Is accurate, 



- 12 - 



is inexpensive, and can "be generally applied. The resiilts so far have 
"been encouraging. 

Of 165,000 women over 20 years of age living in the Memphis-Shelby 
County area, about half have been examined at least onee on a voluntary 
basis. Of the first 70,000 about 1,300 - or 2^ - were considered suspi- 
cious cases. More than a thousand of these women voluntarily had sections 
of tissue taken for microscopic examination, which is the only moans of 
confirming a diagnosis of cancer. It turned out that half of these women 
had cancer of the uterus in some stage. How many of these malignancies 
were unsuspected prior to biopsy? About 60fol Of the women found to have 
cervical cancer — called by some authorities "early stage" uterine cancer — 
close to 90^ were unsuspected prior to biopsy! 

The average age of the women with pre-invasive cervical cancer, when 
compared with that of women in the advanced stages of uterine cancer, 
suggests that the pre-invasive stage lasts long enough — several years, 
that is, — to permit curative treatment if discovered at the yearly checirup. 

This cytologic test is simple and easily applied. It will detect 
cancer in the early stage of development. Therefore, if the technique is 
applied generally on a mass basis, it should be possible to obliterate or 
greatly reduce uterine cancer mortality. In view of the fact that uterine 
cancer represents the second most prevalent type of cancer in women, it 
now appears certain that this project will furnish the datr, necessary to 
launch a widespread and Integrated attack on this disease, 

Pathology 

I have referred to tissue examination as the only means of confirming 
the presence of cancer colls. Pathologists arc the experts and specialis'^s 



,?l i: 



- 13 - 

in this work, and during tho last year they have continued research investi- 
gations concerned with the identification and analysis of malignant lesions 
in hoth experimental animals and human "beings. 

One of the most important recent developments in this field is the 
tissue culture technique which uses cellulose sponge as an artificial 
medium on which cancer cells may reproduce themselves in a 3-<iimonsional 
pattern. This permits the o'bservation of tumor growth and change much as 
it appears in the human "body. This new arrangement of tissue growth is now 
"being used to test specific therapeutic agents against tumor tissues taken 
from the still-living patient, and should provide a more accurate guide to 
the clinician in handling cancer cases. 

In another kind of project, an atlas on transmissablc malignancies, 
giving history, a review of tho literature, detailed morphological descrip- 
tions, and photographs, is being prepared "by oiir staff for puhlication under 
the auspices of the National Research Council. This should he of great 
value in identifying and diagnosing various tumors. 

Our pathologists also provide other Institutes of the National 
Institutes of Health with such services as the processing and diagnosis of 
tissues, analysis of microscopic sections of tumors or suspected lesions, 
and autopsies. Much of this work is done for the Clinical Center. 

This reference to the new Clinical Center "brings mo to a "brief dis- 
cussion of projects, pro'blcms, and plans involving patient treatment. 

General Medicine 

It is largely in the field of general medicine where the researcher 
and the clinician meet to serve the cancer patient. Investigations are 
carried on in two major areas - the effects of drugs on cancer, and the 
meta"bolic interrelations "between the patient and his tumor. 



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One project has tested the comtincd effect of the two most potent anti- 
leukemic compounds known - 6-mercaptopurine and amethopterin. Remissions 
were found to occur in about one-third of the patients treated. The study 
of acute leukemia will be continued, and an attempt is being made to define 
the usefulness of animal Icukemias in predicting what will happen in the 
treatment of leukemia in man. 

In the coming year a major effort is to be made on the problem of the 
chemotherapy of solid tumors. Compounds which have been shown in chemical 
pharmacology studies to have significant anti-tumor activity in animals 
will be evaluated in clinical trials. 

The natural course of a variety of raaligna,nt diseases in terms of the 
use and requirement by the patient of nitrogen, minerals, and vitamins has 
been carefully observed. Those studies will be expanded to attempt a de- 
finition of what it is that the tumor uses and how these materials affect 
the patient. 
Surgery 

Since surgery is one of the only two forms of treatment by which cancer 
can be cured, this is a field in which improvements and refinements of 
technique are continually sought. Our surgeons are investigating the possi- 
bilities of treating advanced lung cancer by means of combined surgical and 
chemo therapeutic methods. They are also studying special surgical techniques 
in an effort to reduce the mortality of advanced cancer of the cervix or 
neck of the uterus. 

Another project of fundamental importance involves the attempt to 
improve the accepted standard surgical methods of treating cancer today. A 
review of the causes of failure in many types of cancer amenable to surgical 
therapy shows that in a significant number of cases failure occurs because 



- 15 - 

of wound rocurrenccs. It is believed that these recurrences develop 'bccauRG 
cancerous cells lodge themselves along the edge of the incision at the time 
of surgery. Search is under way both in man and in animals for means of 
reducing or eliminating such recurrence by carefully washing and otherwise 
treating wounds with specially prepared chemicals during the postoperative 
period • 

In addition to specific research, our surgeons serve the patients re- 
quiring operative treatment in the Clinical Center, and also furnish our 
research people with different kinds of malignant tissues necessary for 
microscopic and biochemical analysis. 

Eadi?.tion 

Research in the field of radiation is particularly important because 
radiation both induces and cures cancer. Investigations under way have been 
noting the effects of small and large doses of various kinds of radiation on 
different kinds of cancers in animals with a view to proper regulation of 
dosage to human patients. Different kinds of radiation affect living tissues 
differently. Experiments with mice indicate that the biologic effects of 
alpha rays from radon arc greater than those from an equivalent dose of 
X-ray. It is now well established from experiments with mice and rats that 
bone marrow as well as ground-up bone is effective in preventing death in 
irradiated animals. Determination of the specific substance which gives 
this prptection and how it operates, is the next step. 

Studios on the protective mechanism in animals damaged by and recovering 
from X-irradiation have indicated that resistance is closely associated with 
tho number of one particular type of white blood corpuscle. It was found 
that mice with their spleens removed were less resistant to infection than 



- 16 ~ 



intact mice as a result of exposure to sublethal doses of X-irradiation, 
Radioactive isotopes have also 110011 studied. One project recently 
established the cffectivoncsg of radioiodine therapy in treating metasta- 
sizing or spreading thyroid tumors if the primary tumor responds to radio- 
active iodine. In another project, through the use of radioactivo-carbon- 
labcllod histidine, evidence is accumulating that liver tumor tissue differs 
from normal liver tissue in the method of building nucleic acid, which ia 
one of the major building blocks of protein. 

As a result of recent developments, the Radiation unit plans to expand 
its program. Not long ago, a 3 million electron volt Van de Graaff genera- 
tor was acctuired as a gift. Two 2 million electron volt machines of the 
Bane type were purchased and are being installed. With the further install- 
ation of more X-ray therapy equipment, the projects and services of the 
branch will be greatly enhanced in terms of typo and number. 

Chemotherapy 

Thanks to the special interest in cancer chemotherapy shown by the 
Congress, it has been possible to give considerable impetus to research in 
this field, and the number of grants awarded to nongovernmental scientists 
and Institutions has been substantially increased. The present research 
grant program in this area involves about 100 projects amounting to over 
$2,000,000 dollars. 

Only 25 percent of all cancer cases are diagnosed while the disease is 
still sufficiently localized to make possible cure by surgery or irradiation. 
As a result of rai^id progress in the search for chemical agents which can 
selectively destroy cancer cells and not harm normal tissues and crgans, 
there is increased hope for oven those patients who were previously consid- 
Grcd incurable. 



- 17 - 

Ovor 12,000 chemical compounds have 'been analyzed. Approximately 500 
tested at the National Cancer Institute have "been found to merit further ox- 
porincnt. Although no cures of cancer have "been effected by drugs alone, 
chemical compounds have proved iiseful in temporarily checking the course of 
the disease and in prolonging the life of many patients suffering from leu- 
kemia, Hodgkins disease, cancer of the breast and prostate gland, and some 
other forms of cancer 

In the managenent of one tj-ijo of leukemia, for example, animal experi- 
ments have shown that cancer cells which develop resistance to or dependence 
on specific compounds may yet become sensitive to other compounds. This 
suggests that when one drug becomes ineffective, treatment may be continued 
with another. This chenotherapeutic procedure has been followed with human 
patients with good and promising results. 

Similarly, with other types of cancer in animals, ten drugs were re- 
ported to have brought about permanent euro, especially in mice and rats. 
Though there was no transference of effectiveness to human beings with cancer, 
these experiments are encouraging, and research in this area is expanding 
both intensively and extensively. 

To assist scientists engaged in chemotherapy research, a program for 
wide exchange of information in this field has been recently established by 
the Committee on Chemotherapy of the National Advisory Cancer Council of the 
National Cancer Institute in cooperation with the American Cancer Society, 
and the Damon Runyon Fund. A variety of activities will be developed 
through this program. Included among them will bei formal conferences and 
symposia on cancer chemotherapy, the issuance of a periodic compilation of 
reports on current research in this field, and the compilation and issuance 
of a bibliography of cancer chemotherapy literature covering the period 



itwnrfii 



- 18 -r 

19/4-6 through 195^^. 

Provision is "being made for individuals and small groups to meet in- 
formally in various parts of the country to discuss inter~institutional 
studies, standards for evaluating chemical compounds, potentially useful 
sutstanccs, and other pertinent au^bjects. One such meeting was held recently 
in Washington to discuss methods of screening compounds, and the pharmacolo- 
gical and physiological aspects of cancer chemotherapy. 

The formally organized Committee on Chemotherapy further plans to tring 
to the attention of investigators those chemical agents which may be of inter- 
est to them and to assist in obtaining chemicals in sufficient quantity for 
evaluation. 

Very substantial progress in the search for drugs effective against 
cancer is confidently escpocted to result from these coordinated efforts. 

G-rant-supportod Research 

Many important research contributions to the problem of cancer are made 
by the nongovernmental scientists whose work is supported by grants of funds 
representing more than 40 percent of the annual budget of the national 
Cancer Institute, 

For example, cancer-inducing substances (carcinogens) have been found 
in certain industries and in the environment - for example, in automobile 
exhaust and air pollutants such as smog - as noted earlier in my remarks. 
The search for more of these carcinogens, and the determination of their 
extent and danger are being supported by grants. 

The role of organic substances such as hormones and enzymes, produced 
in the body itself by the normal or abnormal functioning of organs or glands, 
is also being stxidied by grantees. These substances may be carcinogenic in 



- 19 - 

thonselves or may enhance the tunc r-pro due ing properties of carcinogens. 
For example, it was discovered that chcnically-induced liver tumors in rats 
could be prevented if the pituitary gland was first removed "before the chemi- 
cal compound was given to the rat. However, the administration of pituitary 
hormones to such a rat would pornit the tur.ior to grow. It must te rcmemtorod 
that in all these studies involving experimental animals, especially rats 
and mice, similarities with man in terns of "body functions may provide 
eventual means of controlling cancer in human beings. 

Grant studios of the chemistry of normal and cancerous cells - their 
nutritional requirements, the means by which they grow and reproduce, and 
the factors that control those activities - are providing the basis for 
improved chcmothcrapcutic treatment. 

In the field of cancer diagnosis, a new instrument has been developed 
for more accuratelj' locating tumors inside the body. The Instrument, called 
a somascopo or echograph, makes use of sonar and radar technique to yield a 
picture showing the soft tissue in much greater detail than do X-rays, 

Work is also going forward on the development of a method for the large- 
scale automatic screening of patients for cancer by electrical measurement 
of the abnormally bright fluorescence shown by cancer cells under ultra- 
violet light. Other studies are being done on various blood tests for cancer. 

And of course, new chemo therapeutic compounds are being identified 
and tested. This program has been helped considerably by the development of 
successful techniques for the growth of various human tumors in rats, guinea 
pigs, hamsters, fertilized eggs, and in the test tube. 

New surgical skills have boon developed which in combination with better 

# 

clinical management of the patient permit the removal of tumors previously 
considered inoperable. Excision of various ductless glands has been found to 



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- 20 - 

arrest temporarily the growth of certain inoperable tumors* 

A less expensive type of linear accolorator has "been developed which 
can provide nvLLti-nillion-volt radiation. Cobalt 60 is now used as a radia- 
tion source for the treatment of cancer. 

TRAINING- 

Grants have ■been awarded for several years to approved professional 
schools - nodical, dental, and osteopathic - to coordinate and improve the 
teaching of cancer to undergraduate students. A recent study of the interest 
in and knowledge of cancer acquired hy these young men and women as a result 
of such added materials in the curriculun disclosed a heartening increase in 
the students' awareness of cancer and in his acquisition of background in 
its diagnosis and treatment. In this manner, the general practitioner in 
particular is being more adequately arned. 

A gradual and steady increase in the number of scientists trained in the 
various fields of cancer research is also essential if this disease is to 
bo conquered. As of January 1 of this year, l62 promising young scientists 
are being aided by our fellowship program to secure advanced training in 
cancer research. In the 16 years of the Institute's pre-doctoral and post- 
doctoral fellowship program, some 1,197 young men and women have been 
supported in their training to become research scientists. In addition, 
since 1938, about 865 youjag physicians have received specialized training, 
in such fields as surgery^ medicine, pathology, or radiology in institu- 
tions throughout the country in order to improve the care and treatment of 
cancer patients in hospitals and clinics 



- 21 - 

DISSEMIMTION AND APPLICATION OP KNOWLEDGE 

New knowledge of cancer gained through research must be applied to the 
prolilem as widely and fully as possible. Close relations are riaintained with 
the States through grants to State health agencies in developing cancer con- 
trol programs. We are always ready to assist any type of professionally 
appropriate group through consultation services. 

The prompt exchange of infomation anong scientists is especially in- 
portant to the conduct of research. The National Cancer Institute makes a 
valuable contribution to this need by publishing a bimonthly journal which 
is one of the most important in its field. Exchange of information is also 
encouraged through the attendance of our staff members at scientific meet- 
ings for the presentation or discussion of papers, and through our coopera- 
tion with such organizations as the American Cancer Society and the American 
Association for Cancer Research, 

In view of the high cure rate for most types of cancer if the disease 
is caught in the early stages, an informed and medically cooperative pxiblic 
is essential to the successful control of cancer. Therefore, the Institute 
is engaged in a comprehensive program of public education in the manifold 
aspects of the cancer problem by translating technical medical material into 
non- technical language and preparing articles, bronchurcs, and other types 
of materials for such groups as nurses and health educators, students, and 
for the lay public in general. Such information is necessary and effective 
in exploding superstitions, identifying the truths, and securing the inter- 
ested cooperation of the average citizen. 

In this presentation I have tried to point out briefly the highlights 
of the National Cancer Institute's program of activities during 195^» aJ^d 



- 22 - 

havG attonpted to project its needs and plans for the coning year, I trust 
that ny conncnts have "been helpful in indicating that, no matter how 
gradiial or undranatic the progress, progress has hcen made and will continue 
to he nade hy the Institute in its research assault upon the nysterios of 
cancert As each year passes, more and rioro people are snatched frora death. 
Their pain has heon alleviated. More hope, rather than less, is indeed 
justified that this dread disease can and will he conquered. I wish to 
thank the nenhers of this Cor.inittec for their forhoarance and interest* 
I an grateful for this opportunity to appear hofore you to descrihc our 
projects, our plans, our hopes, and our needs, and I will welcome any quostiona 
you nay have. 



OPENING STATEMENT 
by 
Dr. John W. Knutson, Chief Dental Officer 
Public Health Service 
before 
COMMITTEE ON APPROPRIATIONS 
1956 ESTIMATE 
for 
"Dental Health Activities, Public Health Service" 



Ml'. Chairman and Members of the Committee: 

This appropriation covers activities of the Public Health Service 
concerned with the prevention, control, and treatment of dental disease. 
The term dental disease embraces a >n.de variety of disorders which affect 
more than 90 percent of the American people from early childhood to 
advanced age. Included in this group of disorders are dental caries 
(tooth decay), periodontal disease (pyorrhea), malocclusion of the teeth 
or Jaws, hare lip and cleft palate, and oral cancer. 

COST OF DENTAL DISEASE 

Health officials have begun only recently to recognize dental 
disease as a major national health problem. The dimensions of this 
problem are maasured not only in economic terms, but in its effect upon 
the well-being of Americans. The cost to consumers in this country is 
close to ,1)1.6 billion a year. This means that f}l out of every !Ss6 spent 
for personal health services is expended for dental treatment. In 
addition, governmental and voluntary agencies spend many millioas of 
dollars for this purpose. These expenditures are visible and direct. 
Nevertheless, they account for merely a fraction of the total cost of 
dental disease. 



- 2 - 

Added to these outlays ivS the vast economic burden of lost manpower 
to industry, which according to one study amounted to more than h? absences 
per 1,000 employees a year for diseases of the teeth and gums. Even data 
of this type, however, tend to understate the importance of dental disease 
as a cause for industrial absenteeism. Overlooked arc the many disabling 
conditions traceable to dental infection. Familiar exainples include 
sinusitis of dental origin, iritis associated with infected upper teeth, 
impaired hearing arising from malocclusion, and many instances of severe 
pain and stiffness of the neck. Nor, in this connection, should we dis- 
regard the serious complications which dental infection may cause in persons 
suffering from rheumatic heart disease. Even where the condition is not 
sufficiently serious to keep a person avray from his job, substantial losses 
may occur through impaired efficiency resulting from pain and discomfort. 

Moreover, the widespread occurrence of dental disease has serious 
implications for the national defense. It will be recalled that in 
accwtiulating a military force of some 15^000,000 in World War II, about 
50,000 persons were found unfit for service for dental defects - a loss 
of approximately three military divisions. ^ comparable and equally pre- 
ventable manpower vzastage was again experienced in mobilizing for the 
Korean action. A study of 556,000 men rejected or discharged for physical 
or mental causes from July 1950 to September 1953 disclosed a total of 
more than 17^000 rejections for dental reasons. 

We already knox^r that most dental defects can be corrected by modern 
dental service. Nevertheless, an intensive program of dental research •>.r< 



- 3 - 

is needed if we hope to achieve permanent results in combating dental 

disorders, '^he logical approach to the public health problem of prevention, 
therefore, is through expansion of research. 

DEMTAL RESEARCH 

Research, we feel sure, will ultimately disclose methods not only 
for the prevention and control of dental diseases, but also for improved 
methods of diagnosing and trsatinf; defects that cannot be prevented. To 
this end the National Institute of Dental Research maintains a threefold 
program. In research conducted at the Institute, an atteiiipt is made to 
broaden our understanding of the biology of dental disease and its 
relationships to general health. Through a program of grants, the Institute 
stimulates research in dental schools and other institutions, supporting 
investigations which could not otherwise be undertaken for lack of funds. 
In addition, fellowships are avrarded to assist promising young scientists 
to complete their training and to get a start in dental research. 

Research Grants ; In the face of mounting costs of research and 
increasing needs for scientific personnel, it has become more and more 
evident that Federal assistance is required to assure the conduct of basic 
studios in the various outsid'-- institutions concerned witli expanding our 
knowledge of dental disease. During the past year various research studies 
have been conducted in non-federal institutions with the aid of research 
grants from the Public Health Service. This vrork has included studies on 



- h - 

prenatal influonds on tho production of nalformed teeth and .jawsj tissue 
culture studies on embryonic dental and on salivary gland tissues; on 
heredity as a factor in the causation of dental caries in rats; and on 
the effects on the oral tissues of systemic diseases and chronic environ- 
mental irritation. 

In the process of reviewing applications for research grants, our 
Dental Research Council is afforded an opportunity to survey the status of 
research in dentistry in order to discover neglected areas of research, 
and to encourage the interest and c;fforts of competent workers in these 
fields, '^ho modest increases in funds made available for ros.-sarch grants 
last year enabled us to extend support to several previously neglected 
areas of research, particularly in the fields of unzymology, genetics, 
growth and development, and periodontal disease. 

Research Fellowships : A recent survey by ttie American Dental 
Association of needs in dental education pointed to the shortage of 
trained research workers and teachers. The pre- and post-doctoral 
fellowship program of the Institute assists in the solution of this 
problem. Research fellowships are awarded to encourage promising 
students to continue their training in preparation for careers in teaching 
or raR-.;arch, The increase in funds made available for this program 
during FY 19'^$ ^^Jill undoubtedly yield results. These funds have also 
permitted the inauguration on a sinall scale of a program designed to 
interest undergraduate students in a research career. 



-5- 

Laboratory and field research : Our studies in dental caries are 
being continued in the fields of bacteriology, histopathology, and bio- 
chemistry. Although water fluoridation has given us an effective tool 
for handling part of the problem, we still have much to accomplish for 
our adult and rural populations. An approach of considerable promise in 
the control of caries for these people is through the use of antibiotics 
or chemotherapeutic agents. An intensive search for an effective agent, 
free from such side-effects as sensitizing reactions, is in progress. 
The virtue of antibiotic control lies in its applicability to all age 
groups, as well as its ability to exercise an immediate protective action 
on the tooth. 

These studies are already sufficiently advanced to suggest a 
promising area for investigation - experimentation with germ- free animals, 
Since cariesdoesnot occur in a germ-free environment, the germ-free 
animal will give the investigator a new means of measuring the activity 
of individual types of bacteria in producing caries xjhen introduced to 
the oral cavity. 

Studies of tooth structure by optical and electron microscopy are 
revealing the nature of the caries process, bringing to light the path- 
ways by Tjhich bacteria invade tooth substance, and the manner in which 
the organic and mineral components are destroyed. 

Significant advances are being made in research on the chemistry 
of tooth structure. The resulting knowledge of variations in chemical 



'■■»i. 



composition and properties can subsequently be related to individual 
differences in caries susceptibility. 

Fluoridation of public water supplies as a dental public health 
measure will be reported on in some detail latero As with all programs 
that progress from laboratory - to field trial - to application, there 
remain important areas for investigation which must be continued if 
maximum values are to be derived from major research advances in any 
given fielde Current research at the National Institute of Dental Re- 
search relating to fluoridation is designed to explain how fluorides 
prevent decay and to increase our knowledge regarding the metabolism of 
fluorides 

Periodontal disease, the major cause of tooth loss in adults, 
affects 3 out of 10 of our 30-year-olds, Among the older age groups the 
ravages of pyorrhea are even more prevalent, for as many as 85 percent 
ultimately suffer from this dental maladyp Since elderly persons are a 
large and increasing proportion of our population, it is clear that 
periodontal disease vdll assume even greater significance in the futureo 
The need is therefore urgent to enlarge our efforts to determine the 
basic etiologic factors of this disorder. 

Studies on periodontal disease have already suggested that in- 
fection is subsequent to a noninfective factor, concerning which little 
is known. Progress is being made in the development of fundamental 
knowledge of normal soft tissues of the mouth and of the structural 
alterations associated with other diseases. 



-7- 

Steps are being taken to fill the gaps in our knowledge of the 
epidemiologic characteristics of periodontal disorders. Among our 
noteworthy recent accomplishitients is the foriTiUlation cf a method for 
measuring the occurrence of pyorrhea in large population groups o Much 
knowledge can be gained by observations in a community to discover how 
many people are affected, what types of the disorder are involved, 
and at which age its earliest manifestations are noted. The epidemiologic 
approach, which has been employed so effectively in research on caries., 
should yield definitive information on the factors associated with the 
occurrence of periodontal disease© 

Clinical research; Establishment of the Clinical Center has 
provided an opportunity to bring together the laboratory and the 
clinical scientist. In addition, it has encouraged an interdisciplinary 
approach to research, which is being brought to bear productively in 
our studies of wound healing, of leukoplakia (a precancerous condition), 
and of periodontal disturbances « One project of interest centers on 
methods of simplifying the treatment of malocclusion. This is a con- 
dition in which the teeth are either improperly arranged in the jaws, 
or in which the relationships of the teeth or jaws. are structurally or 
functionally out of balance. Malocclusion often causes serious disfigure- 
ment and loss of function, creating problems in individual adjustment and 
even leading to emotional disturbances. Progress tovTard simplified therapy 
offers a hope of widening the availability of treatment to the 1 out of 



-8- 

every 10 children X'jhose occlusal irregularities are severe enough to 
require orthodontic care. Another project in the growth and development 
field seeks to establish a sound basis for the treatment of cleft palate 
and hare lip, congenital defects foiond to occur once in every 800 
live births. Our cleft palate project is concerned •(^rith investigating 
the role of muscle forces in restoring functional anatomical relation- 
ships, and with the effectiveness of speech therapy and other treatment 
in mitigating psychic injury through early correction of the deformityo 

The broadened attack on periodontal disease will receive par- 
ticuiftr emphasis at the Clinical Center, A method for assessing the 
severity of periodontal disorders has already been subjected to clinical 
trial o It is now being used in a study to determine the systemic 
derangements, such as diabetes and rheumatic heart disease, associated 
with diseases of the tooth-supporting tissues. This approach is being 
facilitated by the ready access of the unusually complete clinical 
records maintained at the Center and the diversity of diagnostic tests 
performed for each patient. 

For the immediate future, data are to be accumulated on the use 
of general anesthesia in oral surgery in order to establish a base for 
evaluating new, rapidly acting drugs for dental use. The Center answers 
our long-felt need for a means of validating clinically promising leads 
from the laboratory. 



- 9 - 

PREVEMTION A.ND CQtlTRQL OF DENTAL DISEASE 

As I have indicated, t?ie Public Health Service is deeply committed 
to the search for new knowledge regarding the cause and treatment of 
dental disease. A corollarj'' concern is in developing effective 
preventive techniques and expediting their application. 

Water fluoridation ; The fluoridation of public water supplies, 
developed after long and painstaking investigation of its safety and 
health-giving values, has been endorsed in principle by all the major 
health organizations of the Nation. It has been definitely shown that 
fluoridated water can reduce caries by as much a s two-thirds. Demon- 
stration that this method of caries control is possible over a lifetime 
at an expenditure of $7 per person is the most outstanding achievement 
of dental research to date. Despite the promise inherent in this 
measure, progress in gaining community acceptance of water fluoridation 
has been slow. At the present time rnly 1,0U0 cities and towns, with 
an aggregate population of 20, It million have adopted the procedure. 
This situation reflects in part the lag between discovery of knowledge 
and its translation into action. The necessary knowledge regarding 
the benefits and safety of fluoridation has been at hand for some time 
novT, It remains only to have this knowledge put to work as rapidly 
and effectively as possible. 

Work is being continued in order to simplify and refine current 
fluoridation procedures, as well as to test the suitability of various 
fluoride compounds. Progress is also being made in determining the 
relationship between climatic conditions and the optimum fluoride 
concentration. It has been shown, for example, that in warm climates 



- 10 - 

fairly lower concentrations afford optimum protection. 

Direct application of fluorides ; At the present time, topical 
application of fluorides is the only established method f or control of 
caries among rural populations lacking central water supplies. The 
most effective fluoride solution and concentration, the optimum number 
of applications, and the simplest method of administerinf^ the applica- 
tions are problems receiving careful investigation. 

Defluoridation studies ; In more than 600 communities, the 
water supplies contain amounts of naturally occurring fluoride 
sufficient to mottle tooth enamel. Appreciable gains have been made 
in solving the problem of how best to remove excess fluorides without 
losing the beneficial effects of an optimum concentration. In studies 
under way at Bartlett, Texas, and Britton, South Dakota, bone char and 
activated alumina show much promise as media for reducing fluoride 
content, 

DENTAL Rn; SOURCES 

The supply and availability of dental personnel have a direct 
bearing upon the Nation's dental health. The most effective use of 
these resources, coupled with a vigorous approach to expansion in the 
years ahead, are issues of singular importance. Until preventive 
dentistry has had years of nationwide application, the large share 
of our control efforts will remain a responsibility of the private 
dentist treating the individual patient. The Public Health Service 
therefore works closely with health organizations, providing important 
advisory and technical services. These activities are directed toward 
maximizing the use of existing resources in personnel and facilities. 



- 11 - 

and toward continuing study of the factors necessary for expansion and 
off active utilization of these resources. 

Manpower shortar;cs ;-- Available evidence indicates a shortage 
of dentists which is aggravated by their uneven distribution. Dental 
schools are currently accomodating capacity enrollments^ producing 
graduates in excess of the number of dentists who die or retire each 
year. 

The growth of population^ however, is outstripping the rate of 
increase of dentists. Should those trends continue, the ratio of 
dentists to population will continue to decline. In order to insure 
orderly planning and development of programs for training of the number 
of dentists and auxiliary workers needed, the Public Health Service 
is collaborating v/ith outsido organizations on studies of the problem. 
Information is now being assembled on the dentist supply of States 
and counties which may be of extreme value in connection with estimates 
of resources i or civil defense and public health activities. A related 
area analysis nearing completion will provide previously unavailable 
material on the supply, professional service expectancy, and patterns 
of withdrawal from the labor force of dental hygienists. 

Since the number of graduates lies at the heart of the problem of in- 
creasing manpower, some of our studies are concerned with educational costs, 
unmet needs for construction and equipment, and strategic location of 
new schools. Of considerable interest to school financing is a report 
on the costs to the student of obtainihg a dental education, which will 
be released during the current year« 



-12 - 

Manpower utilization ^ ■ Particular interest and attention in 
r'icont ycarc have i'ocuGod upon mothodE of extending the rorvice capacity 
of our pi'Gsont supply of denti::^t3. Much of the interest stems from 
findings of our studies, which suggested that most dentists can double 
their output through a more effective use of qualified auxiliary pijrsonnel 
and a more efficient arrangement of equipment. To encourage the widest 
possible use of these labor-saving rae-S;.hods, demonstrations in this area 
will be continued. 

¥e are also moving forward in our observations on methods of 
practice and of financing dental care that may increase the effective 
use of manpower and the volume of dental services. A study completed 
during the past year has made available information on the time and 
service requirements involved in meeting the continuing needs of a 
group for comprehensive dental care. The findings of t'lis study offer 
valuable insights into the naturo and problems of prepaid dental care. 
Our studies in this field will bo broadened to include actuarial^ opera- 
tional, and organizational problems of dental prepayment plans. 

As in other fields of concern with the Nation's health, the 
Public ;Health Service has direct as well as indirect responsibilities. 
In field studies and in intramural research, the Service assesses 
health needs, develops new methods of control, and conducts demonstration 
projects. These are direct responsibilities. A second role is illustrated 
by the stimulus and financial support given to research in other institu- 
tions and agencies. Moreover, States and localities call upon the Service 
for advice and consultation in meeting the day-to-day problems of 
applying existing knowledge of public health practice. This method of 
approach, applied only recently to dental health, has already proved its 



ePENING STATEMENT 

by 
Dr. James Watt 
Director, National Heart Institutii 
Public Health Service 
before 
COMMITTEE ON APPROPRIATIONS 
1956 ESTIMATE 
for 
"Salaries, Expfenses, and Grants, Nattptiel H'='?-rt Institute'' 

( HISTORICAL BACKGROUND ) 

('The budget proposal for Fiscal Year 1956 of the 
National Heart Institute is based upon the current status of 
the several aspects of the Institute's general function, 
established by the Congress, of supporting and conducting 
research and training in diseases of the heart and circulation 
and of aiding the States in the development of community 
programs for the ::ontroI c£ those diseases. 

( Since the National Heart Institute came into being in 
1948, it has through the operations made possible by the 
annual Congressional appropriations! developed into a major 
influence in the nationwide effort against heart disease that 
is making steady and highly encouraging progress on many 
fronts. 

( The National Heart Institute program for Fiscal Year 
1956 is designed to take advantage of the opportunities for 
research and its application that are possible today only 
because of the gains of the past several years. The program 
is oriented toward -che gathering of knowledge and its use 
against congenital heart disease, rheumatic fever and rheumatic 
lieart disease, high blood pressure, and hardening of the 
arteries--the major killers and cripplers of the heart and 
circulatory system. ) 

Mr. Chairman and Members of the Committee: 

THE IMPORTANCE OF THE HEMT DISEASE PROBLEM 

In the changing national health problem of recent years which 

has seen the chronic diseases come, to the forefront, heart disease-- 

lar^e and complex group of ailments of the heart and blood vessels 

--has played a major role. Twenty years ago, less than a third of all 

deaths were attributable to heart disease--420 000 out of 1 342 ,000 

in 1933. Today cardiovascular disease causes more than half of all 



a 



- 2 - 

deaths in the United States--an estimated 730,000 out of 1,470 000 
in 1954. 

Although the major bulk of deaths from heart disease is 
among older persons^ it is far from being a problem only of the aged. 
In 1953 for example of all persons dying from heart disease almost 
a third (31 percent) died at ages under 55. 

During the past three decades the risk of dying from heart 
disease 

(1) has decreased for ages ur>der forty-five; 

(2) has shown little change in the important age group 45 
to 64 for males and females combined; 

(3) has gone down for females 45 to 64; 

(4) but has gone u£ considerably for males 45 to 64. 

The significance to the nation's defense, manpower and economy 
of this most important trend is suriined up in the stark fact that 
Half of all the white males who die in their forties and fifties now 
die of the various form? of heart disease . 

While good data on the prevalence--the amount--Q£ heart disease 
are not available, it seems reasonable to estimate that there are 
not less than 10,000 000 persons in the United States suffering from 
some form of heart disease. For every death from heart disease, there 
are probably many more sufferers alive either severely crippled or 
restricted or certainly not as effective citizens and community 
members as they would otherwise be. 

These facts highlight the importance of the problem of heart 
disease and emphasize the importance of the objective of the National 
Heart Institute program: the reduction of untimely death and dis- 
ability from heart disease and the consequent bringing of added years 
of healthy, productive, and happy living to more and more people. 

That this is a realistic and attainable goal is shown by the 
state of today's knowledge about heart disease in which already 



- 3 - 
some types can be prevented and some cured; in which it has been 
shown that many kinds of heart diGease--either without therapy or 
by medical and surgical treatment, including some formerly considered 
incurable or rapidly fatal, can be reversible ; and in which most 
patients with heart disease can be materially improved by proper 
treatment and management. The programs of the National Heart 
Institute have played important roles in bringing about this progress, 

HEART RESEARCH GRANTS 

The stimulation given by the research grant program of the Heart 
Institute has significantly increased the productivity of cardiovascu- 
lar research. The studies carried out represent research progress 
that would otherwise not be made, since all projects supported are 
in addition to those undertaken by the institutions with their own 
funds. The program does not supplant support from foundations, 
private, philanthropic, or voluntary health organizations, but has 
encouraged continued and increased support by such groups. 

More than 629 research projects currently under way in over 
100 universities and hospitals in all parts of the country are 
receiving support through the grant urogram. These projects encompass 
investigations in both basic and clinical areas related to heart 
disease, with concentration upon major problems such as hardening 
of the arteries and high blood pressure. Following are a few of the 
many achievements resulting from the research grant program. 

Arteriosclerosis : Scientists at the Michael Reese Hospital in 
Chicago have continued investigations related to the sex differences 
in the incidence of coronairy arteriosclerosis. They have found that 
the administration of cholesterol to sexually mature female chickens 
does not produce coronary arteriosclerosis, although the chickens 



- 4 - 
of the same age. The administration of female sex hormones to male 
chickens prevented or reduced the incidence of coronary arterio- 
sclerosis. The female sex hormone, therefore, has been shown to 
exert possibly a protective effect against the deposition of 
cholesterol in the walls of the coronary arteries. 

Another investigator, at the Mount Zion Hospital in San 
Francisco, is establishing the important part played by cells of the 
liver in removing dietary-derived cholesterol from the blood. This 
indicates that abnormal functioning of these cells may be an important 
factor in the production of high blocd cholesterol levels following 
high cholesterol dietary intake. This study contributes information 
regarding one of the fundamental mechanisms for the control of the 
cholesterol level of the blood. 

It is recognized that atherosclerosis can occur in man without 
apparent prior elevations of blood cholesterol or lipoprotein levels. 
Several workers, therefore, are investigating the artery wall itself 
and its relationship to the formation of the lesion. At the Southwest 
Foundation for Research and Education, data are being accumulated 
demonstrating that the aorta (the main blood vessel from the heart) 
is capable of manufacturing cholesterol and lipoproteins. These 
studies are continuing in an attempt to determine what factors 
influence the rate and distributior. of this process. 

The incidence of arteriosclerosis among young people, as well as 
those with advanced age, is continuing to be investigated. The effect 
of diet and environment among people of different genetic background 
is being studied by researchers of Boston and the University of 
Minnesota. A scientist at Lousiana State University has developed 
a new staining technique, which he is utilizing in studies on the 
incidence of arteriosclerosis among young persons in this country 



- 5 - 

and abroad . 

Hypertension ; Fundamental research on the mechanisms of blood 
pressure control continues to be productive. Investigators at the 
Cleveland Clinic have shot/m that plasma from persons with hypertension 
is constrictive to normal blood veasels. The vaso-constrictor material 
responsible, serotonin, has been isolated, crystallized, and structure 
determined. It is now being tested to learn its normal function in 
the body and its possibili;:ies as a contributing factor to the clinical 
entity recognized as hypertension. 

Disturbances in the balance of body constituents known as 
electrolytes (salts) appear related to the mechanism of high blood 
pressure, Clearer definition of the relationship of these electrolytes 
to one another and to the mechanism for the control of blood pressure 
is undergoing investigation at the University of Pennsylvania. At 
Georgetown University, an investigator is studying the effect of drugs 
which appear effective in reducing high blood pressure. He has 
recently reported clinical findings or. a new substance, pentapyrro- 
lidinium (Ansolysen) which appears to be more potent than any drug 
tested heretofore. 

Continuing investigation of the possible part that the kidney, 
the endocrine glands, and the nervous system play in hypertension is 
producing leads that more clearly define the delicate balance of body 
blood pressure control. Only through such research dedicated to the 
better understanding of these fundamental mechanisms can the problem 
of high blood pressure be eventually solved. 

Rheumatic Fever : The first phase of a cooperative study on the 
effect of drugs used in the treatment of rheumatic fever has been 
completed. The second phase, a long-term follow-up of patients on 
whom these drugs have been used, is underway. Investigations of this 



- 6 - 
type are of importance in demonstrating the effectiveness of therapy 
against the chronic invalidism induced by rheumatic fever. Community 
studies on the prophylactic use of sulfonamides and penicillin for 
patients having suffered an attack of rheumatic fever indicate that 
the incidence of subsequent attacks can be markedly reduced in 
populations where these drugs are used prophylactically. 

Aside from the clinical findings indicating the presence of 
rheumatic fever, the need for objective tests of rheumatic activity 
has long been recognized Studies at Irvington House, New York, and 
others, have demonstrated that C-reactive-protein, a material produced 
by tissues in response to inflammation, is an extremely sensitive and 
reliable laboratory test for the detection of rheumatic activity and 
as a guide to the treatment and management of patients with rheumatic 
fever , 

Surgery : An important new method which enables the cardiac 
surgeon to perform operations within the heart has been developed at 
the University of Minnesota. Blood returning to the patient's heart 
is channeled to a donor, circulated through the donor's body where 
it is oxygenated, and then returned to the patient's circulation 
beyond the heart. The heart thus remains relatively free of blood, 
and those anatomical defects which previously seriously interfered 
with the patient's activity and life span can be repaired. This 
technique permits the surgeon to work within the heart for longer 
periods of time than is possible with other techniques. 

Hypothermia, reduction of body temperature, has passed the 

first experimental stages and is now being used to permit operations 

on the interior of the heart, particularly where the valve leaflets 

of the heart have become adherent. Modification of techniques 

developed at Hahnemann Medical College, Philadelphia, are now being 
utilized in clinics throughout the country. Follow-up of patients 



- 7 - 

undergoing operations utilizing these techniques indicate that persons 
whose careers have been interrupted by this disease process are now 
again active members of their corrmunity. 

It has been observed that the heart and vascular system of 
the pig is remarkably similar to that of humans. This animal, 
however, because of its size, has not been suited to laboratory 
experimentation. A pig small enough to be relatively easy to keep 
in the laboratory throughout its entire life span is being developed 
genetically at the University of Minnesota. This animal, with a 
mature weight of about 60 pounds, is now being used in studies in- 
volving repair of cardiac and blood vessel abnormalities as well as 
in diseases caused by viruses affecting these organs. 

R ehabilitation : The field of rehabilitation is hampered by a 
lack of solid and fundamental scientific information about human 
performance. The need for the application of the concepts of the 
methods of the physical and functional sciences to this problem has 
long recognized. A research project studying the factors underlying 
human performance has been initiated whereby the methods of several 
scientific disciplines are being cooperatively focused upon this 
problem. It is anticipated that projects of this type will supply 
the basic material leading to a clearer understanding of ways to 
rehabilitate the patient recovering from cardiovascular disease. 
RESEARCH AND CLINICAL TRAINING 

Research relating to the cause, prevention, diagnosis, and 
treatment of diseases of the heart and circulation is producing 
results which are reducing the disability caused by this group of 
diseases. Continued production of effective results depends upon 
the introduction of new skills and trained personnel in both the 
areas of cardiovascular research and of clinical application of 



- 8 - 
medical knowledge. The Institute's programs are helping to meet 

these needs. 

Research Fellowships : This program, by offering encouragement 
and financial assistance to qualified individuals to enter upon a 
research career in the heart disease field, aids in relieving the 
scarcity of trained investigators. The need for capable researchers 
is a continuing one, since skilled workers, able in the conception, 
administration, and execution of high-caliber studies are few in 
number in comparison to the oppor ;.unitie3 for important research. On 
this activity depends the future core of trained investigators for the 
attack on theamultitude of problems existing in the cardiovascular 
area . 

Training Grants : Teaching grants make it possible for schools 
of Medicine, Public Health and Osteopathy to continue to coordinate 
and improve the teaching of cardiovascular disease subjects to 
students. The need for improvement and expansion has been recognized 
by the schools and the funds made available are utilized by them to 
fulfill the needs of this objective within their local situation. 
Much has been done toward this end individually, and mutually^ 
through meetings of the cardiovascular Teaching Grant Program 
Directors from each institution. • The need, however j continues to 
be a growing one, for as research discoveries are made new methods 
of instruction must be developed to include them, in Order that 
graduating students may enter their professional careers equipped 
with the most advanced knowledge. 

The program also includes training stipend awards to young 
physicians for special training in heart disease diagnosis and 

treatmsHt. This is an essential investment in helping to provide 

the medical care needed by the people of this country. The preseiit 

number of physicians and related medical personnel skilled in cardio- 
vascular techniques, specialized procedures, and methods, is 
seriously inadequate compared with the amount of heart 



and blood vessel disorders in the natiori. Tratiri,-si'g at-f.piajl^-e • 
are providing a means fot partially overcoming this shortage. The 
development of special skills necessary for patient care is important 
to provide for the still increasing nuvnber of persons ^o will 50 to 
their physicians for help because of heart disease, 

NHI DIRECT RESEARCH 

The Heart Institute's program of direct research is aimed at 
the improvement of the prevention and treatment of diseases of the 
heart and blood vessels, This aim is served by 1) the development 
of fundamental information concerning the heart and circulatory 
system and 2) the correlation of such information with existing 
knowledge and new information acquired in other centers of research 
and its application to the treatment of heart disease. These studies 
are conducted on a broad front, utilizing the skills of many disci- 
plines, in order to further knowledge of fundamental biochemical 
and physiologic processes and at the same time to develop the 
■ipplication of such knowlsdge to the treatment of the cardiac patient. 

The accomplishments of the past year represent in large part 
che further development of projects instituted in earlier years. New 
ievelopments in many of these have directed efforts along new channels 
and certain new projects holding considerable promise for the future 
have been undertaken. 

Progress in Arteriosclerosis Studies 

Atherosclerosis or hardening of the arteries is the basic causo. 
of much of the illness and death from cardiovascular disease. When 
located in the coronary arterie? which supply blocd to the be.-rr 
muscle, it may lead to sudden death, to repeated coronary heart 
attacks or to progressive heart muscle damage and congestive heart 
failure, in the large vessels of the extremities it may lead to 



- 10 - 
stoppage of blood flow and the development of gangrene. When athero- 
sclerotic lesions are located in the vessels of the brain they may 
lead to the damage to specific brain regions commonly known as stroke. 

Once thought an inevitable part of the process of growing old, 
it is now established that atherosclerosis is ^^eflnitely a disease 
which afflicts some at a relatively early age, others practically 
not at all. It has further bean established that atherosclerosis 
is associated with certain abnormalities of the handling of fatty 
substances in the body either as a result of defective body mechaniSiaF 
or abnormal fat intake. As a result, deposition of fatty materials 
occurs in the artery walla, initiating the atherosclerotic process. 

Intensive studies of the mechanism by which fatty substances 
are carried in the blood and disposed of by the tissues have been 
under way in the Heart Institute laboratories for some time. These 
hold the best promise of eventually revealing the nature of the 
fundamental abnormality leading to atherosclerosis and pointing a 
way to its prevention and treatment. 

Fatty materials differ from most other body constituents in 
that they do not dissolve to any appreciable extent in water. Hence 
they must be carried in the blood stream attached to other materials 
which keep them in solution. The nucleus for the transport of fat in 
the blood is provided by certain of the plasma proteins. Upon these 
may bo heaped layer upon layer of fatty materials until the individual 
particle may actually reach microscopically visible size. 

A "clearing factor" system whose components have been described 
by Heart Institute scientists acts to strip the fat from these 
aggregates converting them to smaller more stable, and less dangerous 
entities. It has been shown in the last year that this clearing 
system has its primary function In the tissues, presumably making 



- 11 - 

fat available to the cells for their use. Further study of the 
tissue handling of fat may reveal the defect which, in atherosclerosis, 
permits the dangerous accumulation of these fatty aggregates in the 
blood. 

Attention is also being devoted to the proteins upon which 
these fatty substances are carried to determine whether the abnormality 
in atherosclerosis may sometimes be in the nucleus of the particles. 
The proteins are being labelled with radioactive tracers to determine 
whether the protein is the same in the small, normal, harmless fat- 
proteins (lipoproteins) as in the larger ones associated with the 
development of atherosclerosis. Meanwhile studies of patients are 
continuing to further define some of the abnormalities associated 
with the development of atherosclerosis and the effects of a number 
of drugs and hormones on fat-handling in these patients. 

A new technique for the separation of the various fat-bearing 
proteins of the blood has been developed which has two great ad- 
vantages over previous methods: 1) it eliminates the most expensive 
instrument formerly required for such studies and should make possible 
research on blood fats in many places where the expense had previously 
discouraged it; and 2) it makes available for chemical analysis 
special lipoprotein fractions which could previously not be analyzed 
individually; abnormalities in composition as well as amount of these 
fat-protein complexes have already been detected in individuals 
with atherosclerosis. 

Research in Hypertension 

Efforts in the field of hypertension (high blood pressure) 
have been concentrated chiefly on the search for a drug which can 
be used safely and on a long-term basis to keep the blood pressure 
at normal levels in individuals with hypertension. There is good 



- 12 - 
reason to bslieve that such a drug would be effective in preventing ^ 
or reversing the deleterious effects of this disorder. 

The first drug with blood pressure-lowering effects isolated 
in Heart Institute laboratories has been carried through to trial 
in patients in the Clinical Center, The evaluation of this drug, 
andromedo toxin, a substance isolated from Rhododendron leaves, is 
now nearing completion. While the drug may find a place in the 
short-term treatment of certain types of disorder associated with 
acute elevation of the blood pressure (such, possibly, as the 
eclampsia of pregnancy), it seems unlikely that it will be useful 
for the treatment of hypertension generally. This is so because 
its effect is rather short-lived after each dose, because it is 
effective only by injection, and because undesirable effects are 
detected in patients with doses very close to those required to 
lower blood pressure. The latter finding is illustrative of the 
importance of early testing in man in the process of drug development, 
since the subjective toxic effects noted in man cannot be detected 
in animals. It is in such research that the Clinical Center proves 
extremely valuable since this facility is ideally suited for 
carrying out drug studies which include early human testing. 

Although experience with andromedotoxin has been somewhat 
disappointing, a number of other agents, both synthetic and naturally- 
occurring (isolated from plants) , are under study and include several 
promising leads. It must be borne in mind that the development of a 
single new drug useful and dependable for the treatment of human 
hypertension would repay many times over the time, effort and money 
expended on such a project. 



- 13 - 

Advances in Congestive Heart Failure 
The symptom complex known as heart failure may occur as a 
result of any of the major diseases of the heart. The familiar 
picture of breathlessness , of swelling of the ankles and legs, is 
attributable to failure of the heart to be able to carry its work 
load and to the abnormal retention of salt and water by the kl^lney 
which results. The problems of cardiac failure are being attacked 
in several ways. 

A substance in normal blood was shown by a Heart Institute 
investigator to exert an effect on the heart beat similar to that 
produced by digitalis, the drug long universally recognized as 
highly beneficial in the treatment of heart failure. It was thought 
that this material might be a hormone and involved in the regulation 
of the contraction of the heart muscle. Using large amounts of 
.: . liver as a starting material and monitoring each step by determining 
the effect on heart contraction, minute amounts of this substance 
. have now been isolated and some of its characteristics determined. • ;.. 
While its source within the body has not yet been identified and 
its function in the control of the heart beat is not yet determined, 
the isolation procedures which have been worked out prepare the way 
for the preparation of larger amounts sufficient for its chemical 
identification and for studies of its role in the normal and diseased 
heart. 

It has previously been shown by Heart Institute investigators 
that the abnormal retention of salt and water which occurs in ex- 
perimental heart failure is dependent upon increased secretion of 
salt-retention hormones by the adrenal glands, these hormones in 
turn exerting their effect upon 'the kidney. An improved method of 
assaying for these salt-retention hormones has been' developed ;ivu1. 



- 14 - 
applied to the study of patients with heart failure. Increased 
amounts of aalt-retentlon hormone have been demonstrated ir. the 
urine in disorders associated wj.th fluid retention. Studies are 
in progress to determine the normal stimulus which causes the 
adrenal to secrete these hormones so that the nature of the abnormal 
stimulus in heart failure can be evaluated, 

The demonstration of the involvement of adrenal hormones in 
the salt retention of cardiac failure along with the need for a 
drug which can be used to control the retention of salt in cardiac 
patients when taken by mouth has stimulated a new program to discover 
an antagonist to the salt-retention hormones - that is, a compound 
of generally similar structure, so modified as to prevent the action 
of salt-retention hormones and reverse their effects. A large 
number of new synthetic steroid hormones withTaarious structural 
modifications are available from the drug industry as a result of 
their interest in such substances for the treatment of arthritis. 
Arangements have been made to draw on this source of potentially- 
useful drugs and a procedure has been worked out which promises to 
'■.be the first useful test for such activity in animals. 

D rug Investigations 
In the area of the development of therapeutic agents progress 
has been made in several fields. A fundamental discovery deals with 
the mechanism by which drugs are converted in the body to inactive 
products. The latter is the process by which the body disposes of 
'., most medicinal substances and the speed at which such disposal 
progresses limits the usefulness of many drugs because of either 
too long or too short a persistence in the body. It has been found 
that a wide variety of chemical conversions is carried out by a 
small number of similar and closely related enzyme systems. These 



- 15 - 

enzyme systems are fco be found in little-studied submicroscopic 
particles in the liver and the enzymes exhibit an extraordinary 
degree of non-specificity,, The importance of an understanding of 
these mechanisms in the design of drugs for specific actions in the 
body is obvious. It may also be predicted that a finding of such 
fundamental importance will have implications and applications which 
are not yet foreseen. 

The studies of the anti- inflammatory drug phenylbutazone 
referred to in earlier reports have led to further research with 
related compounds utilizing information gained from the study of 
the route of breakdown of phenylbutazone in the body. Several in 
this series show promise in preliminary trial*, yielding the anti- 
inflammatory effects of the parent compound without producing the 
abnormal retention of salt ana water which limits the usefulness 
of phenylbutazone, 

.. A search for improved drugs for the treatpient of abnormal 
heart rhythms has been Intjtttuti^ and a potentially useful group of 
compounds has been uncovered and is uader study. One has been 
discarded, after trial in patients, since it represents no improvement 
over procaine amide, an agent whose usefulness was first demonstrated 
in Heart Institute laboratories. Other anti-arrhythmic drugs should 
be ready for trial in patients in the near future. 
New Surgical Techniques 

In the field of heart surgery, advances have been made in 
the improvement of diagnostic methods. A technique for measuring 
pressures in and obtaining blood samples from the left side of the 
heart has been developed. This makes this portion of the circulacion 
accessible for the first time and makes possible improved identifica- 
tion of abnormalities of the valves and chambers of the left heart 



and.facilitates ' the diagnosis of abnormal communications of the 

left and right side of the heart. • . ■ • 

Several projects in the field of hypothermia have yielded ■ 

significant progress in the last year. Hypothermia, a marked 

reduction of body temperature sometimes referred to as artificial 

hibernation, markedly reduces the metabolism of body cells and 

hence their requirements for oxygen. The circulation can therefore 

be interrupted or drastically reduced for longer periods than are 

possible at normal body temperature without causing irreversible 

damage due to oxygen lack. This can be of great value in the 

repair of certain defects of the heart, since operations can be 

performed under direct vieion. in a bloodless field. 

The usefulness of the hypothermia in cardiac surgery has been 

limited,, however, by the occurrence of serious abnormalitlea of heart 

rhythm. A method of preventing these abnormal rhythms by blocking; 

certain nerves supplying the heart has been devised and successfully 

applied in dogs. After additional experience has been gained in . 

animals, this promising technique should be applicable to human 

surgery. 

; • APPLYING KNOWLEDGE ABOUT HEART DISEASE 
One of the major objectives of the National Heart Institute 

program is to assist communities in the application of what is already 

known to reduce death, disability, and suffering caused by heart 

disease. Grants-in-aid to States and Territories are made according 

to n formula based on the population and economic needs of the States 

for the purpose of encouraging and promoting the mechanisms by which 

community heart programs can be facilitated. 

These grants-in-aid are materially assisting the States in the 

development, improvement, and extension of their total programs. Their 

diagnostic clinic services are being extended and improved through 



- 17 - 
such things as training courses for clinic personnel, the addition 
of social ^nursing^and nutrition services, and the acquisition of 
new and improved diagnostic equipment. Their professional educa- 
tional programs by the use of seminars, work shops, publications, 
and so forth have extended the nevjer knowledge and techniques to 
the practicing physician to help him maintain a high level of 
competency in the care of his patients. 

States have increased the scope of their rheumatic fever 
programs to include preventive measures in addition to diagnostic 
and follow-up services, and to intensify casefinding efforts. 

Assistance is also given to States in technical matters in the 
development; improvement and extension of community programs for 
heart disease control. 

For example, the Service is aiding in the establishment of 
nuclei training centers to provide nurses in practice an opportunity 
to gain knowledge for the prevention, care, treatment and rehabili- 
tation in cardiovascular disease. 

Improved methods of case management can be of help to cardiac 
patients only if they are known and used by the physicians of the 
community. Here the technical assistance program is helping to 
extend the knowledge of new techniques through professional education. 
A series of tape recordings, covisitmting a course in heart sounds 
as a valuable aid in diagnosis of heart disease, were developed 
and distributed through the public Health Service regional offices 
.. to assist physicians in recogr.izing heart diseases in their patients. 

Other efforts in professional education are the dissemination 
of information which will be useful to the treatment of patients 
such as the statement on prevention of rheumatic fever being jointly 
sponsored by the Public Health Service and the American Heart 



- 18 - 

Association; preparation of exhibits for medical meetings, and 
the preparation and dissemination of booklets such as the Low 
Sodium Meal Planning Booklet which is helpful to physicians for 
use with patients. 

The development of better techniques in the control of 
cardiovascular diseases and the evaluation of the present methods 
are also important functions of technical assistance to States. 
The gap between the discovery of new knowledge in laboratories, 
clinics and hospitals, and the final use of this information in 
assisting communities in solving some of their problems in heart 
disease, can be narrowed considerably by community research 
programs designed to test, oil an experimental basis and with proper 
evaluation, many of the newer developments so that considerations 
can be made as to which of these developments can be adapted to 
their heart program. This operational research area of activity 
provides for the development and evaluation of methods and techniques 
for the practical application of clinical research findings; in 
addition, it provides for investigation of some of the public health 
aspects of heart disease. 

PREVENTING RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE 

Particularly illustrative of the opportunities that evolve 
from rescarch--for the application on a wide and intensive scale of 
knowledge--is the area of prevention of rheumatic fever and rheumatic 
heart disease. As indicated in previous statements, the state of 
knowledge today is such that there is a sound basis for a strong 
preventive program, with the. physician the keyatonc and with 
official and voluntary health agencies working together. 

Many thousands of new cases of rheumatic fever still occur 
each year, although the disease has been dcclining--a.t least in 



- 19 - 
numbers of deaths--for some time. The new cases that occur, add 
to a prevalence of unknown but probably large proportions. And 
mortality, moreover, continues to be far higher than it should be: 
some 15C0 children and young people under age 25 died of rheumatic 
fever and rheumatic heart disease in 1953; over 19,000 others above 
age 25 also died from these causes. 

The opportunity for prevention of rheumatic fever through 
public health programs developed by communities in accordance with 
local needs is becoming better known. A great deal is being done 
in a fair number of communities and States in this regard. Much 
of this effort is a result of a cooperative endeavor betwaen the 
American Heart Association and the Public Health Service which was 
initiated in January, 1953, with the icsuanse of a statement on the 
prevention of rheumatic fever. Given wide diaaemination, particularly 
among physicians, the statement detailed preventive methods and 
provided an autheritative platform frr action by health departments, 
..heart associations, medical societies, and other interested groups. 

Today, a new, revised statement on rheumatis fover prevention 
is being issued by the heart association with Public Health Service 
cooperation. This new statement brings up to date knowledge gained 
from research, much of which was supported by National Heart 
, . Institute grants. For example, the statement contains recommendations 
for the use of a new, long-lasting form of penicillin: several of 
the researchers who worked upon this were supported by heart grantj: . 

With the dissemination of the new statement. , there is an 
occasion for an intensified endeavor in rheumatic fever prevention. 
The Service and the /imerican Heart Association have developed and 
are putting into effect new programs, particularly in professional 
and public education, for this purpose; these form an important 



- 20 - 
part of activities for the yuar. New educational materials, such 
as a new health education unit embracing a new motion picture and 
leaflets for the public, form part of this strengthened, joint effort. 
The public health opportunity for this is summed up by Surgeon 
General Leonard A. Scheele as follows: 

"Preventing rheumatic fever can save many more lives and 
prevent or minim.i2e much more heart damage and disability that is 
now being done, although there are underway in a number of communities 
significant efforts in this direction. Many thousands of new cases 
of rheumatic fever still occur each year, and there are many more 
thousands of 'old' cases. An intensified campaign can markedly 
change this picture and forestall much untimely death and suffering. 
Here is a very real and great public health opportunity." 

While space limitations preclude further detailo of this 
activity here, full details can be supplied to the Committee if 
desired. 

******* 

In sum, th«re is underway today throughout the nation an 
attack upon heart disease on research, public health, and other 
fronts; this attack is of eonsiderably greater magnitude than a 
few years ago and is progressing soundly, utilizing the opportunities 
that arise from increasing knowledge to bring better and better 
diagnosis, prevention, and treatment of heart disease. In the 
"nationwide endeavor, the National Heart Institute, through the 
■. support of the Congress, has developed as a major partner of the 
physician, the researcher, and other workers in the field. 

- THE END - 



OPENING STATEMENT 

by 

Dr. Robert H, Felix 
Director, National Institute of Mental Health 
Public Health Service 
before 
COMMITTEE ON APPROPRIATIONS 
1956 ESTIMATE 
for 
Mental Health Activltiss 



Mr. Chairman £,nd Members of the CoEunittee; 

Historical Background 

The National Institute of Mental Health was authorized, 
under the terms of the National Mental Health Act, Public Law 487, 
(79th Congress) July 3, 1946, to provida for research relating to 
psychiatric disorders and to aid in the development of more effec- 
tive methods of prevention, diagnosis, and treatment of such dis- 
orders. The first appropriation was made for fiscal year 1948 
when a sum of iij>2,048,600 was made available to carry on these ac- 
tivities. These funds were administered by the Public Health 
Service's Division of Mental Hygiene, which had been established 
in 1930 to carry on expanded activities under the Narcotics 
Control Act. This Division was abolished when the National 
Institute of Mental Health was formally established in April 1949. 

As the activities of the National Institute of Mental Health 
have begun to bear fruit in terms of promising research leads, 
expanded training of professional psychiatric personnel, and sub- 
stantive technical assistance to the States in the development of 
control programs, annual appropriations for these activities have 
gradually been increased. . 

To carry on and expand the research already begvm, and to 
support increased basic research and a newly instituted program of 
clinical investigation at the Public Health Service's new Clinical 
Center, a total of spl2,095,000 was appropriated for fiscal year 1954. 

Additional support of training and research activities was 
authorized for the cvirrent fiscal year, and funds for support of 
laboratory and clinical studies at the Clinical Center were also 
increased. The appropriation for the program administered by the 
National Institute of Mental Health totaled ^14,147,500 for fiscal 
year 1955. 



■i^ 



NATURE AiO LXTLOT OF THE PROBLEM OF liENTAL ILLNESS 

No quick, reliable and inexpensive method of determining the extent 
of these disorders in the population has yet been devised. The best avail- 
able estimates indicate that a minimum of 9 million persons are suffering 
from mental or emotional disorders or mental retardation. 

At the present time, our only exact measure of the number of people 
in the United States who suffer from a mental illness or an emotional dis- 
order or who are mentally retarded is found in the figures on the number of 
patients who receive mental hospital care and treatment during the year, 
and the n^ambe^ of patients in institutions for the mentally retarded. The 
most recently completed tabulations (1951) show that nearly a million per- 
sons are treated in mental hospitals and institutions during one year. Of 
these 147,322 are mentally retaixied. It is assumed that approximately 
600,000 patients are under care of outpatient psychiatric clinics or pri- 
vate pJxsrsicians , Therefore, apparently a minimum of 7,400,000 people are 
not receiving the psychiatric treatment or rehabilitation services that 
they need. 

Because a large majority of those who receive help obtain it in 
public hospitals and outpatient clinics, the cost in tax funds is nmning 
about ONE BILLION TM HUNDRED nILLION DOLLARS a year (including compensa- 
tion to veterans with neuropsychiatric discharges), and the cost is increas- 
ing at the rate of about one hundred million dollars a year. 

Since records are kept on those under treatment in hospital, clinic, 
or institution, it is basic to a better understanding of the nature of the 
problem that information be compiled and analyzed so that we can evaluate 

- 2 - 



aej..:c 



nvallable eervices, plan vrtsely for aAditlonal or new aervicee, aud find 
out vrhat happens to these patients. Out Bioinetrics uuaff has "been en- 
gaged for several years in working collaboratively irith the States to 
develop euch Information. 

To demonstrate the kinds of iniormation that can be obtained, the 
Biometrics staff of this Institute cooperated with the Warren State- 
Hospital in Pennsylvania on a study designed to find out what happened 
to pationtB over a period of years — from I916 to 19^0, 

The findings reeultine from this study are Intereetlng, encouraging 
and cballeiiging to all irho are concerned irlbh the welfare of thoae who are 
hospitalized for mental illness. They demonstrate that many of the men- 
tolly ill can and do recover, can and do reeiune their places in the ooel. 
iiiunity. This fact is of course well-known to the medical profession but 
not nearly so widely understood by the public at large. The findings also 
demonetrate that the length of hospitalization is being shortened for 
certain typea of mental lllneee. 

The Uarren State Hospital figuree ehow that the probability of 
patients with, i'unctlonal peychosee (psychoeee for which no organlQ basis 
can be found) being released vdthln the first year following aflxalaeion 
to the hospital Increased considerably during the period 19^6-1950 over 
what it had beea..in the preceding yeare beck to I916. 



LABORATORY AND CLINICAL INVESTIGATIONS 

At the National Institute of Mental Health, scientists of various 
disciplines and various backgrounds devote their time and attention to 
solving the problems of mental illness. The research program includes 
both clinical and nonclinical areas of study. Pharmacologists, biochemists, 
and physiologists v/ork together with psychiatrists, sociologists, and 
psychologists. 

Basic research is conducted in the Institute's laboratories. The 
basic research studies, which also involve an interdisciplinary approach, 
are concerned with investigations on the cellular or organ level, animal 
behavior, mode of drug action, effects of social and environmental factors 
on mental health and mental illness. In many of the research projects there 
is collaboration between the basic research and clinical investigations 
staffs. 
Clinical Investigations 

The Institute has organized three laboratories for clinical invest- 
igations: the Laboratory of Adult Psychiatric Investigations composed of 
the Acute Psychiatric Service and the Chronic Psychiatric Service; the 
Laboratory of Psychosomatic Investigations, and the Laboratory of Child 
Research, 

Research with a group of schizophrenic patients on the adult services 
is seeking to improve psychotherapeutic techniques used with psychotic 
patients, and to find out more about the effects of specialized staff or- 
ganization and ward management in the mental hospital. Special studies 
are being conducted on biochemical and EEG (brain wave) phenomena observed 
in the mentally ill. 

- 4 - 



- 5 - 



Clinical Studies of Psychosonatic Illness 

Physicians in general practice estimate that 40 to 50^ of all 
their patients cone to then idth conplaintc that have psychiatric con- 
plications. The Laboratory of Psychosonatic Investigations has been set 
up to probe into the enotional factors v;hich play either a causative or 
contributory role in the developnent of such illnesses as peptic -ulcer, 
diabetes, high blood pressure, and certain types of heart disease. One 
of the principal investigations in this laboratory involves an evaluation 
of the different ways that norr.ial people, psychosonatic patients, and 
schizophrenics respond to psycho logically- induced and drug- induced stress. 
Fron this study, the investigators hope to detemine those factors that 
are inportant in an individual's ability to withstand stress. The effects 
of stressful life situations and the effectiveness of certain tranquiliz- 
ing drugs on peptic ulcers are also under study, A study now being planned 
will be concerned with the relationship betx\reen the severity of diabetes 
and changes in personality. 
Research on Schizophrenia 

Because schizophrenia has filled nore hospital beds than any other 
fonu of nental illness, much of both the laboratory and clinical research 
is on the origin and treatnent of this widespread nental disorder. Scientist 
studying nental illness are in general agreement that schizophrenia is prob- 
ably not one disease \rith the sane origin for all people. For this reason, 
studios of schizophrenia conbine the theory and nethods of a variety of 
scientific disciplines. 



- 6 - 

IJhile great strides have been nade in recognizing and diagnosing 
the sjonptons of the disease, progress has been slower in treatment. 

Intensive psychotherapy is the principal research ind treatment 
nethod of the clinical investigators. Believing that the early relation- 
ship between the mother and the child plays an important role in setting 
the personality stage on which schizophrenia later develops, several 
investigators are carrying on a study in which both the patients and 
their mothers are admitted for treatment together. Early results indi- 
cate that this arrangement allows treatment to proceed at an accelerated 
pace. Confimation of this finding would mean substantial reductions in 
the period of hospitalization and treatment of many schizophrenics. 

Many biochemical and pharmacological studies have also focussed 
on schizophrenia. Increasing attention is being given a number of chemical 
compounds such as Rauwolfia serpentina , chlorproir.azine, and LSD (lysergic 
acid diethylamide-25 ) . The value of these drugs in treating mental ill- 
ness has not been completely assessed, but they have been an interesting 
and useful research tool. 

The Institute's clinical investigators report that there is some 
evidence that Rauvrolfia serpentina and chlorpromazine are effective in 
controlling and treating schizophrenic patients who evince considerable 
anxiety and excitement. They have also obtained more information on the 
action of LSD. This drug causes a psychological alteration in normal 
people and produces a reaction in both acute and chronic schizophrenics. 



- 7 - 

The r.ianner by x\rhich LSD effects theso changes in r.ian is unknown. However, 
when doses of thousand tir.:es greater than the r-j.nute aiuoiints given to nan 
are given to luonlteys, a tenporary blindness results. This observation 
suggests that the action of LSD nay be localized in an area or conponent 
of the brain controlling vision. 

LSD has also been useful in studying certain syr.iptons of schizo- 
phrenia which nay be the result of an organic inpaiment. For instance, 
schizophrenic-like reactions arc sonetir.ios the first signs of brain tunor 
and diseases resulting fron nutritional deficiencies. 

In addition to studies conducted by this Institute over the past 
seven years, 56 research projects on schizophrenia have been awarded 
grants totaling ^i)l, 965,000. 

Two closely related projects which were aided over a period of 
seven years were carried on by the coordinated work of psychologists, 
psychiatrists and social workers. The studies were designed to describe 
the schizophrenic personality in children five years of age and older 
and in adults. Six patterns of schizophrenic traits and behavior ei-.icrged. 
Each of these patterns provided a hypothesis for further study. 

Sono of the inportant contributions of these two projects to 
the general probleu of schizpphrenia nay be sunnarized as follows: 

(1) nore effective tuchniques for recognizing schizophrenia, for differ- 
entiating its sub-forns, for estinating the degree of schizophrenic 
involvcnent, and for predicting the course of the disease in children; 

(2) infomation on the relation between sone environnental forces and 
the ripening of the overt synptons; (3) inferences regarding treatnont 



- 8 - 

that may be effective vith the specific form of schizophrenia under 
consideration. 

On the other side of the coin, refinement of techniques for 
estimating the degree of schizophrenia permits identification of the 
residue of healthy functioning in the patient. This in tiorn provides 
a foundation on which to base treatment. 

The first volume reporting on this study was recently published 
under the title THE SIX SCHIZOPHRENIAS, Reaction Patterns in Children 
and Adults. 
Research in Child Development 

In one of the Institute's wards at the Clinical Center, a study 
is being made of a group of emotionally disturbed boys of ages 8 to 10 
who have presented serious difficulties to their families and communities. 
Little is known about the treatment of such destructive and aggressive 
children. No positive results have been obtained from the psychiatric 
treatment which has been effective with shy, anxious children. 

There has been a move throughout the country toward establishing 
residential treatment centers for such children. The maximum effective- 
ness of such centers, however, depends upon more knowledge about the 
kind of life situation that leads to antisocial behavior and better ways 
of helping the child make a satisfactory life adjustment. Treatment of 
these children involves a study of all the contacts and activities in 
the life of the child to determine their relative importance on his 
total life experience. 

In the brief period of four months since the boys were admitted 
to the Center, progress has been made in treating them, and new data 
which may prove of real significance are being developed. 



- 9 - 

Child studies have received major as well as continuous support 

from the Institute's research grants program since its inception in 

been 
fiscal year 19U8. Over this period grants totaling $3^35^^000 have/awarded 

to studies directly concerned with children. These funds represent over 
2^% of the total research grant funds appropriated during the seven- 
year period. 

The Institute is supporting a wide range of research based on 
the theory that the origins of some of the mental illnesses and behavior 
disorders lie in the formative years of childhood. Most of these studies 
are long-term, sometimes requiring 20 to 25 years to complete. 

One of the earliest studies supported by this Institute has now 
been completed, and a comprehensive report will shortly be published 
under the title MIKffiST AND ITS CHILDREN, A Study in Psychological 
Ecology. 

"Midwest", a real town, is unique because it does not rely upon 
nearby larger communities for its livelihood, services or recreation. 
The project staff report that the town is the center of life for the 
inhabitants and they actively participate in the life of the community 
rather than assume roles as passive spectators. 

Midwest provided a rich field for observation of how children 
develop, behave, and learn to take their places in community life. 
The Midwest study is basic research in human behavior and the psychological 
factors affecting its development. Though ecological studies have tradi- 
tionally been done in the biological and social sciences, this type of 
study is unique in psychology. Because the mental illnesses and person- 
ality and behavior disorders are characterized by difficulties in inter- 
personal relationships and behavior, basic knowledge of the development 
of behavior patterns is essential to our understanding of these disorders. 



- 10 - 

Another study receiving funds from this Institute in the first 
year of the grants program has been completed, and the first of a series 
of monographs on the work has been published under the title EARLY PHASES 
OF PERSONALITY DEVELOPMENT, A Non-normative Study of Infant Behavior. 
Prior to the receipt of our grant, several years had been spent in pre- 
paratory work. The study itself required four years, and additional 
monographs are still in preparation, 

A great deal is known for the period of infancy about functions 
presumably closely related to the process of maturing. However, there 
is little factual information about the great variations among normal 
infants in psychological development. This study conducted at the "iin 
Wenninger Clinic in Topeka was designed to collect information on 
individual differences in functioning assumed to be determined by 
learning and by "constitutional" factors. One of the hj^jotheses studied 
was that variations in infant development reflect significant differences 
in the way in which the infant functions and the general adequacy of his 
adaptation to the environment. 

In order to study infants from a variety of socio-economic groups, 
the research staff obtained the collaboration of the local public health 
department and its Child Health Conferences, 
Laboratory Research Programs 

The Institute's laboratory research program encompasses a number 
of disciplines, including neurophysiology, neurochemistry, pharmacology, 
psychology, and sociology. 

Fundamental studies of the activity of the individual nerve cell, 
the interactions between these nerve cells, and the structure and function 



-'11 - 

of the brain as a whole have led to better understanding of the operation 
of the nervous system. One study, involving the production of a labora- 
tory phenomenon "spreading depression" in the cortex of a cat, has led 
to improved brain surgery techniques and may be of great value in 
determining the origin and nature of the various forms of epilepsy, 

Physical chemists at the Clinical Center are studying the structure 
of nucleic acids and their possible relationship to protein synthesis. 
These studies are fundamental to other work on the role of nucleic acids 
in heredity and the genetic factors in mental diseases. 

Studies on cerebral circulation and cerebral metabolism have 
yielded new information on the relationship between the local nutrition 
of the brain and variations in states of consciousness or kinds of 
mental activity. New insights have also been obtained on the factors 
leading to the decline in function and structure of the nervous system 
with advancing age. 

The Institute's program in cellular pharmacology involves 
fundamental investigation of the manner in wliich drugs and other 
chemicals affect the metabolism and function of cells. This approach 
should contribute greatly to a better understanding of the action and 
use of drugs in man. Further studies of drug action in man, specifically 
the effect of drugs in altering mood states, will also be important to 
developments in psychotherapeutic techniques. If it is possible to 
reduce an individual's anxiety or to increase his inherent assets with 
drugs, the psychotherapeutic procedure of the future may be substantially 
modified for certain individuals. 

Research on animal behavior is essential to a program of mental 
health research. Animals exhibit patterns of development and behavior 



'wliich in many cases resemble those in man. Studies in monkeys' behavior 
have expanded our knovrledgp' of the relationship between the nervous 
system and behavior under varying conditions. Considtsrable information 
has been obtained on the effects of brain lesion on learning and social 
behavior and the development and extinction of neuroses. Results of 
studies of the age changes in the behavior and structure and function 
in the nervous system of rats are being applied to studies of aging 
in humans. 

Psychotherapy, the irajor therapeutic device used in the treatment 
of functional disorders, has been employed for many years, but no firm 
knowledge has been obtained on why these techniques benefit some people 
and have no effect on others. In an attempt to learn more about the 
psychotherapeutic process, several of the Institute's investigators 
are working out the experimental design for the recording and making 
of films of a complete psychotherapeutic process with one patient. 
Methods are being devised for the analysis and interpretation of the 
data so as to improve the effectiveness of this treatment method. 

Scientists examining the social and evironmental factors under- 
lying mental illness have made progress, particularly in schizophrenia. 

Several important phases of the Hagerstown, Maryland, study of 
the distribution of schizophrenia mentioned in our report last year have 
been completed by the investigators in the Laboratory of Socio-environ- 
mental itudies. Contrary to somo current thinking, they have found that 
social isolation during early youth and adolescence is a consequence 
rather than a causative factor in the development of schizophrenia. In 
related studies, these investigators have also confirmed previous findings 
showing that the schizophrenic's mother has typically exercised very 
strong authority, in contrast with the father's weak roiii io the family. 



BIOiviETRICS BRMCE 

Increasing attention is being given to the contributions of biometric 
research in the study of mental illness. The number of States participating 
in the Model Reporting Area for Mental Hospital Statistics sponsored by the 
Biometrics Branch has increased to fifteen, and it is hoped that two or three 
more States will be able to join the Area within the next year or two. The 
Model Reporting Area is designed to enable the States to work cooperatively 
on the development of uniform statistical reporting which will permit mean- 
ingful analysis and comparison. The information that will become available 
through these joint efforts will extend our knowledge of what happens to the 
mentally ill patient in the hospital, point out how his care and treatment 
may be improved, and how the hospital may operate more effectively in the 
interests of the patient. It will also focus attention on areas for further 
research. 

The Biometrics Branch is also setting up a consultative service for. 
the States in organizing new hospital and clinic reporting systems. Another 
great stride has been the development of a nationid.de reporting system for 
outpatient psychiatric clinics. These data will provide basic information 
on the operation of this essential mental health facility. 

In cooperation with the Warren State Hospital in Pennsylvania, the 
Biometrics Branch made a study of outcome of treatment of first admissions 
to the hospital. Based on the records of the Warren State Hospital during 
the period 1916-50, the study provides information by different time periods 
of admission on the probability of a patient of a given age and diagnosis 
staying in the hospital, being released, or dying in the hospital. Such 
facts are important in gaining commtmity acceptance of the mental hospital 
as a dynamic, medical facility. 

- 13 - 



THE MEKTAL HOSPITAL 

Today we are experiencing a newly-awakened public interest in the 
therapeutic management of mental illness. One of the advances in thinking 
in this field is the recognition that the mental hospital, whether well or 
poorly run, is a therapeutic institution offering asylum in the best sense 
of that word to those who are unable to live in the community. It will be 
many years before we can hope to have sufficient professional personnel to 
staff the public mental hospitals according to present standards, but there 
is much that can be done to improve the therapeutic environment that the 
hospital provides. 

As one method of expanding our limited resources, this Institute 
has aided a study of mental hospital procediires and settings. A report 
of the observations has just been published in a volume entitled THE MENTAL 
HOSPITAL, A Study of Institutional Participation in Psychiatric Illness and 
Treatment, 

The study had three major objectives: to find out how the patients 
live together; how the hospital works,* what might be done to make it work 
better aiid speed the recovery of patients. The study demonstrates that 
regardless of the Individual patient's history, at least some phase of his 
illness is affected by the functioning of the hospital as a social unit. 
Other mental hospitals may be challenged by this study to take a look at 
their own policies and procedures and find out whether there are ways to 
improve them for the greater benefit of the patient. 



- U- 



GROWING DEmi^lD FOR MENTAL HEALTH SERVICES, TRAINING, 

AND RESEARCH 

The upsurge of interest in the problem of mental health has sharply 
increased the demand for services to individuals, for research, and for train- 
ing increasing mi.Jj^ rs of professional personnel. The history of this growing 
interest can be summarized briefly. 

At the direction of the annual Governors Conference, the Council of 
State Governments cooperated with the States in making and publishing two sur- 
veys: CENTAL HEALTH FROGRAMS OF THE FORTY-EIGHT STATES, and TRAINING AND 
RESEARCH IN STATE MENTAL HEALTH FROGRAMS. 

In February of last year, the first National Governors Conference on 
Mental Health was held in Detroit. A 10-point program adopted there set goals 
for the States in developing more adequate mental health services, in expand- 
ing trrining opportunities and in initiating or expanding research programs. 

The Southern Governors Conference, of which 16 States are members, 
directed the Southern Regional Education Board to survey the training and 
research resources, existing and potential, and report back to the Conference. 
With the aid of a grant from the National Institute of Mental Health, the sixr- 
vey of resources in the 16 States was completed last summer. The November 
meeting of the Southern Governors Conference adopted recommendations for con- 
crete action by the member States individually and through inter-State com- 
pacts. As the program develops, graduate students will be able to receive 
their professional training in their own or a neighboring State where their 
skills are so greatly needed for services, teaching and research. 

Similar regional programs are underway in the New England States, the 
Midwestern States and the Pacific Coast area. These actions on the part of 
the States demonstrate the deep interest of the public in moving more rapidly 
on all fronts. However, the movement is necessarily geared to the availability 
of trained personnel, now in short supply. 

_ 1 K _ 



- 16 - 

Incr e asing the Supply of Trained Perao nnel 

Through grants to universities and other training centers to stimu- 
late the expansion of training programs and provide traineeships to 
graduate students, the National Institute of Mental Health is providing 
concrete help toward the achievement of clearly defined objectives. 

In developing the training grants program with the advice and 
assistance of the non-Federal experts who constitute the National Advisory 
Mental Health Council and its Training Committee, choices had to be made 
to use our resources as effectively as possible. Taking first things 
first, our efforts were directed toward strengthening the training and 
increasing the number of trained people in the basic mental health pro- 
fessions—psychiatry, clinical psychology, psychiatric nursing and psy- 
chiatric social work. 

Today, there is a crying need and a growing demand not only for 
people from these professions, but for people qualified to work on prob- 
lems which constitute subspecialties of the broad mental health problem — 
juvenile delinquency, mental deficiency, alcoholism, drug addiction, the 
problems of aging, the problems of mental hospital administration and 
the like. 

The Institute staff are working with the universities and other 
training centers on some of these subspecialties to define the training 
program needed and facilitate its development. One of the projects under- 
way is focused on the preparation of mental hospital administrators. The 
goal is to design the kind of; training program the physician needs to 
promote maximum effective use of mental hospital services. 



- 17 - 

The training of professional personnel to work with the mentally 
defective individual and his family is also of paramount importance. Many 
of these retarded children can be helped to become self-sustaining members 
of the community if their handicap is diagnosed at an early age, their 
abilities and limitations carefully assessed and appropriate training 
given to them. Others with more severe handicaps can be helped to lead 
a more satisfactory life in the limited area in which they must live. 

Training for the mental health field, therefore, not only becomes 
a matter of training in the four psychiatric professions but includes 
special training in psychiatric concepts and the dynamics of human be- 
havior for professional people who are immediately concerned with some 
of the problems previously enumerated as "sub- specialties." Such special 
training by its very character adds to the nimber of people who can make 
a real contribution in the broad spectrum of community mental health 
services. 
State and Community Services 

The ultimate objective of all efforts in research and training 
is to provide new knowledge, new techniques, new skills and well-quali- 
fied professional personnel to the States and communities throughout the 
country so that mental illness may be controlled, and sound mental health 
fostered in every individual. 

Before the passage of the National Mental Health Act, there were 
only 24 States which had mental health programs, though all 48 States 
had to provide hospitals and institutions for the care of the mentally 
ill and the mentally retarded. Today all 48 States, the four Territories 
and the District of Columbia have mental health programs in addition to 



- 18 - 



hospital service. Because many of the programs were so recently created, 
they are in various stages of development. 

In fiscal year 1954-> a total of ;i)15, 000,000 was available to the 
States for community mental health services of which i,'p2,325,000 repre- 
sented Federal grants, and Cp2, 270,000 were private funds. 

In the current fiscal year, withthe same amount of Federal grants, 
22 States and Territories have the same amount of money they had in 195Aj 
2-4 reported an increase of 10^ or more over 1954 and 7 States had a de- 
crease of 10;>^ or more. Five States and the District of Columbia have 
budgeted a total of nearly ^600,000 for alcoholism treatment and con- 
trol programs. 

The Community Services staff at the Institute and the psychiatric 
consultants assigned to the Departmental Regional Offices handle as many 
requests for professional consultation and technical guidance from the 
States as they can. However, the new impetus to these programs from the 
actions of the various State Governors conferences and State legislatures 
have greatly stepped up the number of requests received. There is, in 
addition, need to develop nev/ techjiiques for providing mental health 
services more effectively and for demonstrating control techniques. 



• t 



OPENING STATEMENT 

by 
Dr. Victor H. Haas 
Director, National Microbiological Institute 
Public Health Service 
before 
COMITTEE ON APPROPRIATIONS 
1956 Estimate 
for 
"Microbiology Activities, Public Health Sorvico" 



'-'.Tt Chairman and Members of the Committee: 

The National MicrobiolO;'i;ical Institute was created 
in 19)i0 by consolidating those labor/itories within the 
National Institutes of Health which conducted .research on 
the infectious and parasitic diseases. These laboratories 
were the oldest in the Institutes, some having been in 
operation from the very beginnings of the original Hygienic 
Laboratory. Scientists workin;;; in these laboratories, and 
in the Institute of which they are now a part, have made 
many significant contx'ibutions to the advances in the diag- 
nosis, treatment, control, and prevention of the infectious 
and parasitic diseases, A program of clinical investigation 
was added in Fiscal Year 19Sh) and grants in aid of research 
in appropriate fields are administered by the Institute, 

Under the 1956 budget, the National Microbiological 
Institute will operate at essentially the same level as in 
Fiscal Year 1953'. Small increases are requested chi'..;fly to 
provide for activating additional beds i.n the Clinical Center 
and an accelerated poliomyelitis vaccine testing program. 



Scope o f Mic robiolo fjy 
Microbiology is the study oT microorganisms: viruses, rj.ckcttsiae, 
bacteria, fungi, protozoa and parasitic worms. In the National Micro- 
biological Institute attention is focused on tliose species vrhich cause 
human disease. In practical application, microbiology embraces also 
the study of animals which serve as hosts and vectors of disease-produc- 
ing microorganisms. Such animals include insects, birds, aquatic animals, 
and mammals, one of the latter being man. 



2 - 



Mag;nitude of Infectious and Parasitic Diseases 
In the United States, the majority of illnesses are caused 
by microorganisms. This is true in spite of the phenomenal advances 
in prevention and treatment of infectious and parasitic diseases 
which have marked the present century. The common cold, and similar 
infections of the upper respiratory tract, are still the most 
widespread and frequent of all diseases in this nation. Diseases 
of the gastrointestinal tract — particularly the infectious diarrheas- 
are only a little less common. Our children (and their parents) must 
still suffer through many of the common infections which their an- 
cestors have had to bear since the beginning of history, e.g. 
measles, mumps, chickenpoX;, bronchitis, bronchopneimonia, polio- 
myelitis. Though many of the killing infections can now be pre- 
vented, treated, or controlled, there remain many microorganisms 
which have stubbornly resisted all our modern methods and drugs. 
People in the United States still die of pneumonias, urinary tract 
infections, streptococcal disease, virus infections, diseases pro- 
duced by fungi, and other infections and parasitisms which we are 
often powerless to deal with. Even leprosy, the scourge of Biblical 
times, has not been eliminated from our country, and often resists 
even our most modern treatment. 

Abroad, many diseases weaken or kill our friends and allies^ 
from time to time some of them cause us grave concern because of 
their possible introduction into this country. The current year 



- 3 - 

has seen some startling developm3nts in the spread of yellow fever 
northward through Central America and into Trinidad. The best 
scientific minds of our time are mystified at the way in which 
a great epidemic disease will sometimes appear dormant for decades^ 
and then suddenly undergo a sharp and ominous recrudescence, 

A research attack on the microbiological diseases that 
continue to impose a crushing burd-.^r. of suffering, despair and 
economic deprivation is a matter of direct interest to this country 
for several reasons. First, as noted above, there is the problem 
of preventing the introduction or a reintroduction of some of these 
diseases into this country. Second, the study of agents causing 
these diseases is intervroven with the whole body of research in 
microbiology. Third, we have troops in most parts of the world, 
and the regions in which heavy troop movements may be necessary 
cannot be predicted. Fourth, research can increase the physical 
ability of large population groups to do a full day's work. This 
vjill enhance the economic position of underdeveloped countries 
and redound to the benefit of this country. Fifth, medical re- 
search devoted to solution of the major disease problems of these 
countries is a potent and feasible means of winning friends through- 
out the world. 

Program of the National Microbiological Institute 

The program of the National Microbiological Institute is based 
upon fundamental studies of the physiology, metabolism, and genetics 
of microorganisms, and upon investigations of the effects which they 
produce upon the cells, tissues and organs of the animals (particular- 
ly man) which they infect. It extends beyond fundamental studies in 



- l4 - 

the laboratory, providing opportunitins for skilled scientists to 
follow up the leads from basic research by experimental trials in 
the field, the community, the clinic, and the hospital ward. 

Progress in microbiology is continuing at a fast pace. With 
years of sound achievement behind them, scientists in the Microbio- 
logical Institute are confidently looking forward to exciting new 
discoveries. New knowledge and techniques are constantly being 
applied to problems in the infections and parasitic diseases which 
thus far have eluded solution. Fundamental information on the effect 
of microcrganisms on the intimate biological mechanisms of the infect- 
ed cell is rapidly increasing^ it v/ill have practical significance 
far beyond the problems of specific infectious diseases. 

Advances and Problems in Research on Viruses 

There has been a great surge forward in the field of virology 
during recent months. The viruses are the smallest forms of lifej 
indeed, it is questionable whether they are completely living in 
the sense that higher organisms are. They produce many diseases in 
man, and are in the aggregate responsible for more illness in the 
United States than any other disease-producing agent, or group of 
related agents. In particular, they rauao many of ftu? jllno^sos 
of children, some of which piuduce permanent disability. Virus 
diseases include the common cold, influenza, poliomyelitis, measles, 
mumps, German measles, encephalitis, and some types of pneumonia. 

The sturi^'- o.f vji'uses, originally stimulated by use of the 
chick embryo, was further facilitated a few years ago by use of 
immature rodents (mice, rats, hamsters) for producing the necessary 
quantities of relatively pure virus in the laboratory. During the 



- 5 - 

year just past, there lias been an enormous development of tissue 
culture techniques for this purpose. Not only has the method 
proved far better than anything previously available, but practi- 
cal results have materialized rapidly. 

One of these, the development of experimental vaccines against 
poliomyelitis, has been the outstanding accomplishment in the infec- 
tious disease field during the past year. This has been a long 
step forward in our attack on this crippling infection. Scientists 
of the Microbiological Institute have been active in this field for 
many years. The transmission of poliom3''elitis to mice, accomplished 
by one of the Institute's scientists, initiated the current wave 
of progress in poliom.yelitis research. Another significant and 
more recent contribution was the discovery that virus could be 
successfully established by direct inoculation into the spinal 
cord of the mouse. The testing of one of the present experi- 
mental vaccines for safety and potency has occupied a consider- 
able part of our resources during the current year, and technical 
methods are now being developed for assuring both the safety and 
the potency of commercially-produced poliomyelitis vaccines which 
are quite likely to appear xfithin a few months. 

Another advance in the virus field has occurred in respect 
to the viruses lA'hich inliabit the respiratory tract of m,an. The 
Institute's scientists and other investigators supported by N'MI 
grants have been leaders in this work, and are now isolating and 
studying many nevj viruses of this sort. Some are being inoculated 
into hum.an volunteers, and recently completed investigations indicate 
that these studies are already leading to more exact recognition of 



- 6 - 

the nature of soma of the "fevers of undet^^rmined origin." The 
tool which has made these advances possible has been tissue culture; 
the combined skills of the laboratory scientist, the clinical inves- 
tigator, and the epidemiologist have forged the successful product 
of this research. One clear-cut epidemic has been studied thorough- 
ly enough to permit the clinical definition of a specific disease 
not hitherto identifiable, the isolation of the causative virus, 
and the demonstration of antibodies in the blood of persons after 
recovery from infection. 

The viruses of this now group have been named APG — for 
adenoidal, pharyngeal, and conjunctival, referring to bhe fact 
that they are recovered from these particular tiscues (nose, throat, 
and eyes) of man. 

Concepts about viruses are being clarified. Scientists are 
learning that there are many more viruses than anyone has hereto- 
fore suspected. Some of them apparently inhabit man foi' long 
periods without producing disease. A number of them can be demon- 
strated only after prolonged growth of human tissues outside bhe 
body. Yet under some circumstances, viruses of this sort can cause 
illness and even widespread epidemics. The Institute's scientists 
and independent workers supported by research grants from the Insti- 
tute are now making significant contributions to this new knowledge 
of how viruses can behave in such different ways. 

Progress of this sort generates still greater progress. 
Problems in virology that have long awaited solution are being at- 
tacked vigorously. There is no satisfactory treatment for virus 
diseases, and no adequate means for preventing many of them. The 



- 7 - 

new understanding of how viruses behave, and what influences 
changes in their behaviour, provides a rational means for attack- 
ing the diseases produced by these agents in man. Beyond this 
immediately practical goal, scientists are getting flashes and 
glimpses of now comprehension in regard to the basic relationships 
of the virus and the cell which it inhabits, and of whose intri- 
cate life processes it must at one stage of its development become 
an inseparable part. The not too distant goal is an accurate 
understanding of what can cause a cell to go wrong, and how. 
Whien scientists can tell this, the answer will have a profound 
effect upon our conquest of human illnesses, far beyond the infec- 
tious and parasitic diseases. 

Research in Parasitic D isea ses 
While progress in virology is leading the field in micro- 
biology, there are advances in other areas which promise to be 
useful in the ultimate control and treatment of many infectious 
diseases. A promising field for research, which the Microbiological 
Institute has now entered, concerns the effect of bacteria and 
other such micoorganisms upon the larger parasites of the protozoal 
group (single-celled animal parasites). Preliminary results indicate 
that parasites which ordinarily produce disease may be harmless in 
experimental animals vjhich are entirely free of other microorganisms. 
One of the least understood areas in microbiology concerns the way 
in which various microorganisms antagonize, interfere with, or 
augment one another. The recent observations on germ- free animals 
add another substantial segment to the structure of organized know- 
ledge now being built up about this problem. Ultimately, it will 



- 8 - 

be possible to use microorganisras more and more to man's advan- 
tage in the conquest of disease^ this has already been accomplished 
in the field of antibiotic drugs, and in agricultural and many in- 
dustrial procedures. 

Opportunities are increasing for defining the causes of 
many diseases of previously unknown origin. Recent vjork has shox-/n 
that the parasitic protozoan known as Toxoplasma is res;DonsiblG 
for many cases of a serious eye disease (uveitis) which often re- 
sults in blindness. This cui^ious microorganism is widely dis- 
tributed in lower animals; it is capable of existence in man with- 
out producing disease, but under circumstances stil], to be explained 
can cause severe illnesses in addition to the eye conaition just men- 
tioned. The prevention of those disabilities depends upon acquiring 
more knowledge about the parasite, how it gets into the human, why 
it sometimes causes disease and sometimes does nob. Since the 
greatest danger is to the unborn child of a mother who harbors 
the parasite temporarily, and x\rithout any c^vidence of infection, 
control and prevention of damage must be based on fundamental under- 
standing of the life history of the Toxoplasm.a. 

While the broad problem is under intensive study, scientists 
in the Microbiological Institute have recently made two discoveries 
of very practical significance. One was the demonstration of the 
organism, in certain diseased eyes, thus proving its association 
with the affliction it had been suspected of causing. The other 
was the successful employment in a human case of treatment pro- 
cedures developed in laboratory experiments with animals. The 
National Institute of Neurological Diseases and Blindness has. 



- 9 - 

as will ba reported, studied other aspects of this disease. 

Congenital In fe ctions 

Another cause of damage to the unborn child was found 
several years ago to originate from German measles, a normally 
mild disease. These two examples of serious harm to a child still 
in the uterus suggest that other infections, as yet ujirecognizod, 
may cause similar disaster. This problem is receiving more consid-jra- 
tion as a result of the disclosures about toxoplasmosis. 

An intriguing experimental observation reported by Institute 
scientists in the past year indicates that in.fection of the mother 
during pregnancy influences the ability of the offspring to develop 
protective antibodies in response to infections acquired after birth. 
This phenomenon, demonstrated in laboratory animals, emphasizes further 
the potential influence of infections upon the unborn child. 

There are many congenital illnesses and abnormalities whoso 
causation requires explanation; investigators wj th our now clinical 
program are studying some of those conditions with a view to clari- 
fying the possible role of infections. 

New Opportuni ties in Microbio logy 

Never before have scientists in microbiology so expanded 
their interests beyond their own fields of personal specialization. 
This is a good omen for progress. The virologists are becoming inter- 
ested in problems ranging from parasitology to cancer; parasitologists 
are working across their usuil boundaries to contribute to basic cellu- 
lar biology and biological interrelationships of microorganisms; 
epidemiologists are applying their talents to the identification of 
illnesses of unknown causation. The physiologist and the geneticist 



- 10 - 

find intriguing opportunities in bacteriology 'md virology. The 
clinician turns from the bedside to the tissue culture laboratory 
in his attempt to define a patient's illness and to treat it most 
effectively. As basic knowledge increases and comprehension 
widens, scientists in microbiology arc beginning to develop common 
goals vjhich can be perceived by many vrorkcrs with different training 
and backgrounds. As these goals are 'ipproached from many points of 
departure, they become clearer, and their attainment j.s facilitated 
by the exchange of information derived from the different points of 
view. 

The m.omentum of present advances in microbiology is influenc- 
ing scientific research throughout medicine and public health. The 
results now coming froin the laboratories — and those anticipated in 
the future — will not only widen enormously our comprehension of man's 
relationships with the teeming microscopic life about hiia and v.dtliin 
him, but will surely enable us to achieve mastery over many illnesses 
as yet unconqucred. 



OPENING STATEIffiNT 

3y 

Dr« Victor !!« Haas 

Director, National Microbiological Institute 

Presented in Behalf 

of 

Gorgas Memorial Laboratory 

Before 

COM"IITTEE ON APPROPRIATIONS 

1956 Estimate 

For 

Gorgas Memorial Laboratory- 



Mr, Chairman and Members of the Committee: 

The Gorgas Memorial Laboratory, research branch 
of the Gorgas Memorial Institute of Tropical and Pre- 
ventive Medicine, was established in Panama to serve 
as a permanent home for the Laboratory, which was 
named for General Gorgas in recognition of his many 
contributions to the control of diseases prevalent 
in the tropics. The Laboratory was set up in Panaraa 
so that the benefits of its research might be applied 
primarily to the prevention of tropical diseases in 
the population of the Republic of Panama, the Canal 
Zone personnel, and the military forces stationed in 
that area. 

An annual appropriation to finance the Labora- 
tory's research progr.ara has been made by the United 
States Govornraont since 1929. Because these activi- 
ties had been greatly expanded during World ¥ar II 
and because a number of projects of special interest 
to the Army had not been completed. Congress amended 
the original Act in 19li9. The authorized amount 
which could be appropriated annually was increased 
from the original 050,000 to a figure not to exceed 
|15 0,000, 



One of the major studies of the Gorgas Mem.orial Laboratory 
concerns jungle yellow fever in Central America, This disease, 
absent for decades, appeared in Panama in 1914-8 in epidemic form 
and has since spread northward as far as Honduras, Present 



-2- 

indications are that jungle yellow fever will continue its 
prosont course and perhaps reach Mexico, 

The past year has also seen the occurrence of yellow 
fever in the northern part of South America and the Island 
of Trinidad, off the coast of Venezuela, Health authorities 
in Trinidad met the threat by laiinching an intensive program 
to vaccinate the entire population. 

The Laboratory's yellow fever studies, initiated in 
19^1f are aimed at determining the insect carrier or carriers 
of the virus in Central Americaj whether animals other than 
monkeys might serve as reservoirs for the virus j and how the 
virus survives through the dry season when the known mosquito 
carriers are not present. In this program the Central American 
countries concerned are supplying excellent assistance to the 
Gorgas Laboratory, and the Pan jlmeri.can S,anitary Bureau is 
also actively interested in the yellow fever work. In the 
United States, health authorities arc concerned with the dir- 
ection of spread of yellow fever because of the fact that our 
Southern states contain species of mosquitoes capable of trans- 
mitting the disease. 

Malaria control studies by the Laboratory have shown 
that the response of mosquito carriers to DDT -treated houses 
may point to important changes in the malaria situation. 
Mosquitoes now observed in treated villages are hyperactive 



^>'i.''"'r?:- 



\rst. : 



1C:r.rf'V 



vfS.; 



■■■■■ <?■.';■• iACif::i;;: 



-3- 

and apparently do not remain on the treated surfaces long 
enough to obtain lethal dosages of DDT, Plans have been 
made to study this peculiar phenomenon, but the Laboratory 
has been \inable to start investigations because of the pres- 
sure of the work on yellow fever« It is worth noting that 
laboratory tests have demonstrated that mosquitoes caught 
in dwellings are still just as sensitive to DDT as those 
maintained in the insectary and never exposed to DDT, 

Inasmuch as DDT spraying of living quarters is now 
being wj.dely employed in manj^' parts of the world to control 
malaria, the Laboratory's findings on the reduced effective- 
ness of DDT are of great interest to health authorities every- 
where — particularly in view of the fact that the pi'oblem con- 
cerns factors other than the emergence of DDT-resistant 
mosquito populations. The Laboratory is also cond\icting an 
antimalarial drug testing program among natives, but this 
work has not been under way long enough to report on its 
progress t 

Studies are continuing on leishmaniasis, a disease 
which is prevalent in Latin America and many other parts of 
the world. Since the work began, the Laboratory's scientists 
have built up a collection of sandfly specimens embracing 60 
species. As a result of this work new knowledge has also been 
acquired concerning other biting insects in the area. 



■■^"-'f'i,,;-, -, ,.,. 






'■■'■ •;-;;:.•* 



Under its present leadership^ the Gorgas Memorial 
Laboratory hopes to expand its virus work and to establish 
a registry of pathological spociinons on the tropical diseases 
of the area, as well as continue its present activities. 

During the past year, a careful study of the Labora- 
tory's program was made by a United States committee at the 
request of the Surgeon General of the Public Health Service » 
The commd.ttce unanimously recommended that the Gorr^as Labora- 
tory be continued in operation. This opinion was based on 
the substantial accomplishments of the Laboratory over a 
period of years — accomplishments all the more remarkable in 
view of the small amount of money e:q3ended in its operation. 
The committee felt that the Laboratory is conducting a vig- 
orous program, and under appropriate leadership should have a 
bright future. 



OPENING STATEFJENT 

by 

Dr. Pearce Eailey 
Director, National Institute of Neurological Diseases and Blindness 

Public Health Service 
beforti 
COI'MTTEE ON APPROPRIATIONS 
1956 ESTIFlATE 
for 
"Neurolog7 and Blindness Activities, Public Health Service" 



Historical Background 

The National Institi.te of Neijrological Diseases and Blindness 
is the youngest of the National Institutes of Health, having been 
established by Public Law 692, August 1950. No appropriation, however, 
was mads to activate the Institute until fiscal year 19^2, when 
$1,250,000 was made available to initiate a beginning program of 
research in the broad field of neurological and sensory disorders. 
These funds v>rere allocated within the general appropriation "Operating 
Expenses, National Institutes of Health, P.H,3. 1952." 

During fiscal year 1953, '/l,9'''2,rC0 was appropriated to pro- 
vide for essentially the same program as the previous year, the bulk 
of the funds going to the support of research activities in medical 
schools and universities. 

To fijrther the original plans of the Institute, to capitalize 
on expenditures to date, and to begin to meet the rising urgency of 
more research in this relatively neglected area, the fiscal year 195U 
appropriation of '[1,500,000 carried, for the first time, the National 
Institute of Neurological Diseases and Blindness as an identifiable 
appropriation item. 

In fiscal year 1955, the Institute's appropriation was raised 
to $7,600,500 thereby permitting extension of its programs in clinical 
research and in research training. 

Mr* Chairman and Members of the Committee: 

mTURE AND INCIDENCE OF THE NEUROLOGICAL Affll SENSORY'"' DISORDERS 

The seriousness of the neurological and sensory dis- 
orders as a public health problem has been made known to 



^'^Disorders of vision and hearing 



2 - 



Congress in previous years. The salient facts are these: 

1) Some 20 million persons in the United States are affected 
by some 200 of these condi.'ions. The most familiar, 
though not necessarily the most serious, of the neuro- 
logical disorders include cerebral palsy, muscular 
dystrophy, epileps;/', multiple sclerosis and cerebral 
vascular disease (stroke) 3 the most familiar sensory 
disorders include glaucoma, cataract, uveitis and 
diabetic retinopathy. 

2) These disorders are the third leading cause of death 
in the United States and the first cause of permanent 
disability: some 10 million victims are gravely 
crippled by these conditions. 

3) The vast majority of these disorders are incurable and 
only a few are treatable. 

The degree to which these disorders affect the public interest 
economically has not always been evident. It may seem obvious that 
vxhere a vast number of persons are disabled over a large, if not 
total, portion of the normal life span, their care and welfare must 
place a special r.- economic burden on society. But only recently has 
some documentation of the relative costs of the neurological and 
sensory disorders begun to emerge. This has been made possible by 
a study still in progress under the auspices of the NaTiOWj-iL COlilJlTTElii 
FOR KESLaKCH in NiiUrtOLGGICiiL DISORDERS.-''' 

The studj' initiated by the Committee is still incomplete, and 
the facts presented here represent only a portion of those which will 
illuminate to what extent the neurological and sensory disorders 



''""The National Committee for Research in Neurological Disorders has 
been mentioned before Congress in past years. Composed of representa- 
tives of the leading voluntary health organizations in the field, it 
now acts as a unifying force for defining research needs and development 
throughout the nation. Its constituents include the National Society 
for Crippled Children and Adults, United Cerebral Palsy Association, 
National Epilepsy League, United ILpilepsy Associations, National Multiple 
Sclerosis Society, National liuscular Dystrophy Associations, and the 
American Academy of Neurology. 



- 3 - 

presently constitute a burden to the Federal Government and the 
forty-eight States. The data herewith presented represent the 
Committee's analysis of statistics published by the Bureau of 
Public Assistance, the Office of Vocational Uehabilitation and the 
Children's Bureau, 
Tm TOLL TAILM BY THL ili.UKOLOGICAL Ai'ID Si.NSOHY DISORDERS 

In 19$1, some 200,000 persons with various disorders were 
receiving public assistance funds from the majority of States, Of 
these, more than half , or more th;in all persons with all other 
disorders combined , were victims of the neurological and sensory 
disorders. The average cost of their assistance xms more than 
•2,500,000 monthly. 

Not including the blind (also the research responsibility of 
the Institute), i.who receive almost as much assistance as recipients 
suffering all other conditions, the numbers of those with neurological 
disorders alone ranked second (29 percent) only to heart disease 
(31.9 percent). It is noteworthy, however, that heart disease was 
only more prevalent in the age group ip$ or over. In the two other 
age groups, 35 and under and 35 and over, neurology patients ranked 
first with 51.3 and 35.U percent of the total respectively. 

These last statistics suggest that neurological patients are 
long-term patients, and indeed tius is confir'med by the fact tliat 
these patients represent U6 percent of the total (more than any 
other group) who had endured their disabilities for a period of 10 
years or more. 



- u - 

The personal and family trageuy, including the economic drain, 
involved in these disorders is also revealed in analysis of the 
statistics indicating the numbers of those on public assistance who 
were bedridden, chairfast or housebound. In these areas, the neuro- 
logical disorders oven^helmingly represented the leading cause for 
total removal from the social and economic scene with Ul.l percent 
of the bedridden, ^0,5 percent of the chairfast and 35 percent of 
the housebound. 

The pex-sonal degradation caused by these disorders could also 
be measured by statistics, for neurological patients represented 
6U.8 percent of all those needing aid in eating, $$.h percent of 
those needing aid in dressing, and 55.1 percent needing toilet 
assistance. 

I'Jhile the facts and figures on persons receiving public 
assistance are the most complete, data from the Children's Bureau 
and the Office of Vocational Piehabilitation present substantially 
the same picture of overwhelming need on the part of those suffering 
the neurological and sensory disorders. Of the more than ,pU2,000,000 
spent by the States and Federal Government for services to children 
with a variety of disorders, more than k6 percent was allocated for 
aid to children disabled idth cerebral palsy, epilepsy and other 
disorders of the brain and spinal cord, and disorders of the eye 
and ear. 

Of lj.8,983 receiving vocational rehabilitation in 1953 (not 
including somewhat more than 12,000 persons receiving such assistance 



- 5 - 

because of unspecified accidental injuries) j 11^308 or approximately 
2k percent X'/ere victims of the neurological and sensory disorders, 
more than any other single category. It is perhaps appropriate to 
mention tliat many patients idth these conditions cannot be candidates 
for vocational rehabilitation because their diseases are progressive 
or because crippling is so severe as to make useful vocational train- 
ing unfeasible, 
THE. SCIENTIi^C aTTaCK ON THE liEUhOLOGIGAL AiTO SENSORY DISORi^EuS 

To the major problem posed by the neurological and sensory 
disorders, science has only recently bi'ought to bear its Irnowledge 
and desire. The reasons for delay have been mentioned before; among 
them, the reluctance of the crippled victim to press for aid where 
such pressure might only call attention to his disability , not his 
need; and the reluctance of science to challenge the vast complexities 
of the central nervous system where more open pathways of productivity 
lay before him and, more important, xirhere funds were available to 
exploit them. 

The growth of the voluntary health organizations in this field 
has been central to ansvjering both of these problems. These agencies 
could speak and bring care for the victims. They could even provide 
some support ior the scientists. Ith the gathering accumulation 
of knowledge about the nervous system and with the development of 
new tools for the exploitation of further knowledge, the way was 
cleared for a full-scale attack on the neurological and sensory 
disorders. 



- 6 - 

The first major vehicle foi" this attack, however, only came 
with the establishment of the National Institute of Weurolo;_ ical 
Diseases and Blindness in 19^0. As the first national Institute 
devoted wholly to research and research training in the neurological 
and sensory disorders, there can be no question of its significant 
role in medical history, 
SUCCESS OF THE .hTThCK ' 

In last year's testimony, some sure signs of that role were 
already indicated. The first important increase in appropriations 
for fiscal year 19Ii>3 had been marked by a comraensurate rise in the 
Institute's productivity and tlie productivity of its grantees, ihile 
increased support and increased scientific productivity can never be 
in direct correlation, the Institute is again pleased to inform 
Congress that the increased appropriations for 19!^U were again 
followed by research achievements of a high magnitude. 

It is perhaps significant that of some forty "highlights" in 
medical science of the past year as appraised by Science Service (of 
vrhich only twenty were concerned with medical research), Institute- 
conducted or supported research was represented by four accomplish- 
ments. In terms of individual health and the national economy, \je 
feel these four achievements the most important. They are; 

1) A m.ethod for the almost total pi-evention of retrolental 
fibroplasia, the leading cause of blindness in children. 

2) A method for the treatment of granulomatous uveitis caused 
by toxoplasmosis, a disease responsible for from 5 to 7 
percent of blindness in adults. 



- 7 - 

3) A method for the improved treatment of acute and chronic 
glaucoma, thereby aiding in the control of a disease 
responsible for 20 percent of all blindness. 

h) The further development in the treatment of epilepsy by 
glutamine and asparagine. 

EPILEPSY 

Last year, the Congress was inform.ed that discovery of basic 
metabolic defects responsible for epileptic seizures had been .made . 
by an Institute scientist. This discovery provided the first rational 
basis for the treatment of epilepsy and opened up nex-/ avenues for 
research on the brain. 

Of three metabolic defects, it was considered that the epileptic's 
inability to maintain glutamic acid at normal levels within the brain 
cells was probably the most important. On the basis of this considera- 
tion, experimental therapy of epileptics V7ith glutamine (the amide of 
glutamic acid) and asparagine, a closely related compound, was insti- 
tuted. The results of tliat experimental therapy on several patients 
x-rith frequent, uncontrollable seizures were made known to Congress i 
seizures were greatly reduced or eliminated and the epileptic EEG 
patterns often were improved. 

On the basis of this discovery, the Congress in June 19Sh 
appropriated ^750, 000 for a more intensified investigation of glutamine 
and asparagine so as to obtain a more decisive answer as to their 
efficacy in controlling epileptic seizures. These appropriations 
permitted the purchase of these expensive compounds in amounts which 
would allow for expansion of the study at the Clinical Center and for 
the award of grants for similar studies at other institutions. All 



- 8 - 

studies -rwould. encompass enough patients in total so that results at 
the end of a yeaf might be considered statistically adequate. 

At this point, the elaboration of the glutamine-asparagine 
studies are well under way. Five medical schools now are participa- 
ting in this collaborative effort for a year's period.'" Their clinics 
and hospitals are assessing asparagine therapy on a total of 100 
patients with all types of epilepsy; they are working under a single 
research protocol formulated by the Institute but reviewed and agreed 
to by all investigators in careful discussion. 

The Institute's OTcjn assessment of glutamine-asparagine therapy 
at the Clinical Center has been expanded to a total of twenty-four 
patients, only two of vihom, however, have received treatment for a 
year; two for more than six months, A total of fourteen have been 
on either or both compounds for at least two months, and on the basis 
of data now at hand, there is no reason to revise our feelings of 
optimism as indicated last year. 

All fourteen epileptics have been victims of frequent, persis- 
tent seizures, ranging from one to fifty attacks a day. A variety 
of anti-epileptic medications have failed to control these attacks. 
Under asparagine aand glutamine treatment, however, three patients 
are essentially seizure-free, nine have had their attacks reduced by 
60 percent or more, and only t\iro show equivocal responses. As a 

*See appendix A for participating medical schools and investigators 



- 9 - 

result, some child patients have been able to resume schooling (one 
boy having been saved from institutionalization) and adult patients 
have been able to secure and maintain gainful employment. 

AS mentioned last year, we found that glutamine and asparagine 
were easily absorbed into the brain. In establishing maximum thera- 
peutic dosage schedules mth any medications, it is essential to 
evaluate their degree of concentration in the body. Therefore, part 
of our basic research is devoted to determining the concentration of 
glutamine and asparagine in the bloor' and spinal fluid. We shall 
expect to have refined a practical method for this test within the 
next six months. 
RETftOLMTAL FIBROPLASIA 

Last year, the Congress vras infomed of the Institute's 
special capacity to meet special research needs as they occurred, and 
the Institute's initiation and support of a broad collaborative study 
of retrolental fibroplasia was cited as one such case. This clinical 
study, finally encompassing more than seventy-five investigators 
working at eighteen hospitals, had been established in order to confirm 
or deny striking animal experimentation conducted by an Institute 
grantee. Its breadth had been compelled by the urgency for obtaining 
as rapid and decisive an answer possible to a serious problem. 
Retrolontai fibroplasia, a progressive disorder of the blood vessels 
of the retina, primarily occurring in premature infants weighing 
3-| pounds or less at birth, has caused some 8,000 cases of total 
blindness since the disease was first reported in 19U2 by Dr. T. L. 
Terry, 



- 10 - 

The preliminary findings of the retrolental fibroplasia study- 
have now emerged and there can be little doubt that the results con- 
stitute the most important single clinical advancement in ophthalmology 
during the past decade. Announced last September at the annual meet- 
ing of the iimerican Academy of Ophthalmology and Otolar^Tigolof.y, tne 
findings v/ere unequivocal that oxygen - the o.:<ygen routinely adminis- 
tered to premature infants in their incubator - was -'.efinitely 
associated i-ri.th the cause of retrolental fibroplasia and tiiat ox^/pen, 
thei^efore, sliould be administered to premature infants only in times 
of severe clinical crisis.'"" 

The results of this study have been made Icaown to piiysicians 
and hospitals throughout the world. Because some children v/ill still 
have to receive o^cygen for clinical crisis, a fevf will probably still 
incur retrolental fibroplasiaj a few othtrs ijiil develop the disorder 
for causes still to be explored. On the basis of results so far 
announced, however, only about 10 percent of those who suffered it 
in the past will suffer it in the future. 

The cost to the Govex''nment of this study totalled >l|0,000, 
and another ;>11,000 was added by tiro voluntary agencies. The 8, JOO 
children already blinded by retrolental fibroplasia will, during 
the course of their normal life span, cost the States, the Federal 
Government and several welfare organisations ;^i)100,000 each for their 
education, training and support, or a toLal of ^800,000,000, But 
after their lifetime, the tragedy of long life without sight because 

'See appendix B for brief review of cozifirming statistics 



- 11 - 

of retrolental fibroplasia will have virtually ceased and so will 

the heavy economic burden to the Nation. 

UVEITIS 

At the same scientific meeting at which the results of the 
retrolental fibroplasia study was presented, an Institute investi- 
gator in the Bethesda program also presented a paper of intense 
interest to the gathering of ophthalmologists from all over the 
United States and Europe. To this audience came the first report 
anywhere of a treatment for a form of granulomatous uveitis, an 
incurable infection of the back of the eye, especially the retina, 
vrhich is responsible for 5 to 7 percent of blindness in this country. 

VJhile results were preliminary, they seemed promising. Of 
29 cases admitted to the Clinical Center with granulomatous uveitis 
caused by the parasite Toxoplasma, 2? cases had responded to a therapy 
with two drugs - pyrimethamj.ne (Daraprim) and sulfanilamide. Of the 
remaining four patients treated, three had not been treated long 
enough for final evaluation. 

The success of this therapy is still to be determined. Further 
tests viill show whether the drugs are a cure or a controls it is 
still possible that the infection vdll recur, requiring further 
treatment, Daraprim, moreover, in the heavy dosages required in 
the therapy of granulomatous uveitis, causes loss of appetite and 
consequent loss of weight, /hile this side effect is reversed when 
treatment is terminated, possibly some other drug will be found just 
as effective but less toxic. ITiatever the final answer to these 



- 12 - 

problems are, they are somewhat academic to the patients who have 
already received treatment at the Clinical Center. Their vision 
has either been restored or improved, and those who had lost their 
jobs because of failing vision have either regained them or found 
new ones, 
GLAUCOJIA 

This year also saw the advent of another drug added to the 
armamentarium against ej'-e disease - Diamox, a specific for acute 
glaucoma and a useful supplement for other drugs in the treatment 
of other forms of the disorder. Glaucoma is a condition characterized 
by increased pressure of the fluid in the eye which gradually shuts 
off the blood supply to the retina. The results, unless pressure 
can be relieved: permanent damage to the retina and permanent 
blindness, as it now is for more than 55,000 persons in this country. 
In last year's testimony, the research leading to the rational 
use of Diamox against glaucoma was reviewed after the testimony proper 
and inserted in the Record. It had been found that Diamox (a 
sulfonamide derivative) could inhibit the activity of a certain 
enzyme called carbonic anhydrase. Tliis enzyme is responsible for 
the formation of sodium bicarbonate in the Intraocular fluid of the 
3y eye, and sodium bicarbonate is associated" with that accumulation of 
intraocular fluid in'^the eye characteristic of oriaucoma. It was 
thus that last year Diamox was first tested for glaucoma and first 
found to be of particular value in reducing the pressure- in acute 
glaucoma, thereby permitting the intervention of surgerj'-. 



- 13 - 

It vras then thought that Diamox was relatively limited; it 
seemed that lowering of the intraocular pressure could be achieved 
for only a relatively short period of time. Studies by other grantees 
this year, however, indicate this limitation does not exist, for with 
refined methods of administration, Diamox has proved to be effective 
in the long-term treatment of chronic glaucoma, the most common form 
of the condition. Possibly the most significant factor in the find- ■ 
ing of Diamox lies in the fact that it is the first drug yet discovered, 
to inhibit the formation of intraocular fluid, and it thereby sets 
the pattern for an entirely nexj course in pharmacological investigation 
which will almost certainly lead to the development of more successful 
antiglaucoma agents. 

In good part, the problem of ^ilaucoma is one of early detection, 
for found early and treated early, glaucoma should blind only infre- 
quently. Partly responsible for the higher incidence of blindness 
from this disease is the failure of the average individual to obtain 
regular eye examinations; and almost equally important is the inability 
of the average practitioner to diagnose the condition at its incipience. 

Solution of this problem is now at hand with the development of 
a simple instrument devised for the general practitioner--the Berens- 
Tolman tonometer, itested gently on the eyeball (after the adminis- 
tration of local anesthesia), it simply records x\rhether the intraocular 
pressure is high or low — but not precisely how high or low, as do 
more specialized instruments now in use. If the pressure is found 



- lU - 

higher than normal with the Berens-Tolman tonometer, eye examination 
by an ophthalmologist is indicated to determine the exact nature of 
the condition. 

At the present time, some 200 to 300 ophthalmologists in the 
United States and burope are training general practitioners to use 
this instrument and in so doing have alrear^,/ proved its enorm.ous 
practicality. Some ij.0 percent of those patients already referred 
to trained ophthalmologists because of abnormal register of the new 
tonometer have proved to have incipient glaucoma. 

These four advances mark'-the more dramatic developments in the 
Institute's programs during the past year. Lany major problems still 
concern us and it is to be expected tliat for such problems as cerebral 
palsy, muscular dystrophy, multiple sclerosis, and cataract a series 
of progressive steps lie ahead before the final aci-iievements in 
prevention and treatment are obtained. That tliis year saw many such 
steps taken iras perhaps as heartening and Important as the clear 
clinical accomplishm.ents so far mentioned. 
CLiiEBRAi. PaISY 

The House Subcommittee on iippropriations for the Department 
of Health, Education, and Vjelfare has alread;/ received a complete 
review of the extensive, nationwide attack on cerebral palsy being 
spearheaded by the Institute, There are txro broad purposes in tlij-s 
collaborative effort: 1) to establish a more precise determination of 
fetal, environmental and medical factors leading to the various 
forms of human cerebral palsy, and 2) to definitely link the various 



- 1^ - 

symptoms of this group of disorders to the causative brain damage, 
in the first instance, we expect to create a sound rationale for care 
of the pregnant mother and newborn child in order to prevent cerebral 
palsy. In the second instance, our understanding of basic nervous 
system control over motor (muscular) activity should lead to more 
etiological clues, to a radical irprovement of methods of rehabilitation, 
and to the development of new surgical techniques or new drugs for 
improving the performance of the cerebral palsy patient. 

Significant individual developments made during the last 
year focus on studies of brain damage as it occurs during intrauterine 
life. Because brain damage to the child most often occurs during the 
cliild's embryonic growth, the creation and study of experimental cerebral 
palsy in animals provides the bost Oj.-portunity for assessing the 
causative factors leading to several clinical types of cerebral palsy. 

As mentioned last year, experimental jv-ray irradiation of 
pregnant rats has indicated that various cerebral palsy symptoms 
which appear in newborn rats can be controlled. by varying the time 
of irradiation during gestation. Institute experiments in creating 
experimental cerebral palsy by anoxia (oxygen suffocation) confirm 
the fact that the time of embryonic brain grovrth is central to the 
kind and degree of brain damage achieved. The institute has also 
been able to devise a technique for producing anoxia in selected 
fetal animals without damaging the litter mates, thereby permitting 
comparative evaluation of the cerebral palsied animal and his twin 
"normal" after birth. 



- 16 - 

Brilliant studies by a ^^antee cast iurther light on tne 
underlying, causation of cerebral palsy. Studies on the developing 
brain of animals indicate that the significant energy producing 
enz^Tne systems of the brain manifest different levels of activity 
during gestation. These enz;Tne systems lie latent during certain 
periods of brain development, but burst into critical activity at 
specified times. Preliminary studies indicate that alteration in 
the biocherrdstry of these enzymes at those speoifitd times is responr- 
sible for certai. n symptoms of cerebral palsy. If such results 
prove consistent, they will mark the first nope towards achievj.ng 
reversal of the abnormal changes occuring during pregnancy probably 
responsible for brain damage. 

Other progress in cerebral oalsy : (a) bhe refinement of surgery 
for the treatment of severe involuntary mo^ements. (b) the finding that 
the immature liver's inability bo detoxify bile is partially respon- 
sible for the development of kernicterus, thereby sugf^esting the 
possibility for preventing the disorder as well as treating it,"' 
(c) the development of a new research attack on nerve regeneration (because 
nerve regeneration of mammals occurs in utero but not postnaLally, the 
possible biochemical changes involved in this ciiange are being investi- 
gated.) 



'"Last year's test-'mony presented the results on the development of a 
treatment of this disease, previously responsible for causing 10 percent 
of cerebral palsy in children. 



- 17 - 

liULTIPLE SCLJTlOSIS 

The research attack on multiple sclerosis up until five years 
ago had in good part been limited to experimental therapy and several 
thousand drugs have hopefully been tested on this disorder. As it 
must, this trial and eri'or approach continues, and the hopes of 
multiple sclerotics were again raised by a report this year that the 
antitubercular drug, isoniazid, had proved useful in the amelioration 
of symptoms in several multiple sclerosis patients. 

To obtain a decisive ansvxer which would either provide more 
definite rationale for isoniazid therapy or whic:i would stem the 
growing and possibly dangerous use of isoniazid by multiple sclerotics, 
the Institute immediately initiated a pilot project for objective 
evaluation of the drug. This project is not yet concluded, but 
preliminary results should be available within the near future, 
'iilhatever the results, establishment of this "double blind" clinical 
trial has set it he technique for rapid evaluation of promising but 
unproved results achieved at other laboratories where facilities do 
not permit complete exploitation of their observations. 

It seems clear that the most successful developments in the 
attack on multiple sclerosis must come through an understanding of 
the basic mechanisms involved in its causation. Several methods of 
approach presently obtain as a result of recent findings and others 
undoubtedly will develop. It has been found, for example, that 
where myelin is destroyed during the course of multiple sclerosis 
(this is the main pathological process of the disease), the small 



- 18 - 

sujportinj,, cellB oi' the nervous systein (nob nerve cells themselves) 
tend to disappear. These supporting cells, which are called 
oligodendroglia, are believed to play some role in the formation 
and nutrition oi' myelin, and further studies at the Institute xdll 
attempt to clarify this association. 

The problem of myelin structure and activity is at the core 
of the research attack on multiple sclerosis, and tnis research is 
just now becoming productive, IMle it had previously been believed 
that the myelin sheath was simply a protective covering for the nerve 
fibres, we now iiave reason to believe ib plays sn active role in the 
conduction of the nerve Impulse. 

The nerve impulse passes along the nerve fibres in association 
with the interaction of two cheroicals, sodium and potassium. As 
transmission of the impulse occurs, potassium iri.tlxin the nerve cell 
leaves the cell 3 sodium outside of the cell enters. l\ recent report 
indicates that in certain nerve fibres not sixeathed ijith myelin, 
potassium loss from the cell is some 2^ percent greater than in 
those nerve cells i/hose fibres are myelinated. The unmyelinated 
fibres, moreover, perform less activity, more slowly, than myelinated 
fibres. In snort, this finding would strongly suggest that myelin 
seems to have something to do vrith retention of potassium within 
the cell and tiiereby with the speed and activity of the nerve impulse. 

It should be mentioned here that the study of idultiple sclerosis 
has been hampered by our inability to create the disease in animals. 



- 19 - 

A recent report indicates that a canine disease, apparently sindlar 
to nultiple sclerosis in humans, occurs ^dtU some frequency ajiiong 
Boxer dogs, and this exciting possibility will be explored further. 

Last year, it was mentioned that progress had been obtained 
in devising a diagnostic test for ruultiple sclerosis, which liitherto 
has talcen an average of six years to identify medically. Abnormal 
elevation of gamraa globulin in the spinal flui'-l of multiple sclerotics 
is the basis of this diagnostic test, and tiiis year improvements have 
been made at the Institute and by a grantee in the development of a 
simple method for protein-spinal fluid concentration so that anaJ-ysis 
of gamma globulin levels may be facilitated, frelimnary data also 
indicates that ratio of gamraa globulin protein to spinal fluid may 
relate to the progressive course of the disease and thereby provide 
us with a method for establishing prognosis, 
IflSCULii.t ^JYbXnO.^ilT AND riJlJ..Oi;USCUj^'u. DISOhDE^.S 

In the last fiscal year an important se;i,meat of the institute's 
program at the Clinic^al Center has focused a broad attaclc on neuro- 
muscular disorders, which, by themselves alone, constitute a serious 
public health problem. Some of these disorders, muscular dystrophy 
and myasthenia gravis, can be rapid killersj while others, mj/ositis 
and neuritis, can be chronic cripplers. Lieuromuscular disorders may 
arise anywhere along the neuromuscular axis from the muscle to the 
brain. Thus, in muscular dystrophy, the pripiary pathology is in the 
muscle; in myasthenia gravis there is a failure in chemical trans- 
mission at the ooint where the nerves become imbedded in the muscle. 



- 20 - 

(nerve -muscle junction) | and in infantile paralysis and other forms 
of myelitis the damage takes place in the spinal cord. 

Except for infantile paralysis, clinical research in neuro- 
muscular disorders was relatively nonexistent before the activation 
of this Institute in 1951. The causes of these conditions were 
unknown and no fruitful clues to pursue them had been established, 
IJhen the Institute's program at the Clinical Center was started in 
1953, the task of solving the problem of muscular dystrophy aiid 
neuromuscular disorders was as imponderable as piecing together a 
picture puzzle in which most of the essential parts are missing. 
This meant that the research slate developed thus far had to be i;iped 
clean and the fundamentals of these conditions had to be attacked on 
many fronts by adapting to the prcblem nevjer techniques which have 
been developed in biophysics, biochemistry and pharmacology. 

Therefore, the Institute investigators began their Bethesda 
program in neuromuscular disorders by developing new methods for 
studying human muscle biopsies and the chemical nature of neuro- 
muscular transmission J by constructing aew devices for determining 
neuromuscular electronics j by perfecting a method for evaluating 
the ionic exchange of sodium and potassium through the use of un- 
stable radioisotopes! and by the application of the principles of 
flame photometry and chromotography to the problems of neuromuscular 
disease. 



- 21 - 

During the last fiscal year these ne;..r instruments and methodolo- 
gies uwere perfected and used on patients \ath muscular dystrophy, 
myositis, myasthenia gravis, dystropldc myotonia, and farrdlial peilodic 
paralysis. A group of neuromuscular disorders were tested rather than 
the muscular d/strophy alone so tliat if they all iiad some common 
denom.inator, it would not be missed. 

With perfection of new instruments and new technics, last year, 
came the discovery that the muscle cells in muscular dystrophy could 
not retain a normal amount of potassiim and were overloaded vdth sodium* 
vias tills the cause of muscular dystrophy, or was it the consequence 
of some deeper process inherent to the disorder? a careful study using 
ra-lioisotope tracers iias revealed that the potassium deficit is a con- 
sequence, not a cause, so the scientific probe has continued, i-.ecently, 
this team of institute investigators have discovered another abnormal 
metabolic disturbance in muscular dystrophy; the e xcx-etion of abnormal 
amounts of a pentose sugar by patients vdth this disorder, the 
significance of x,rhich is presently being examined, 

ifnile the Instituoe's clinical researcii tearn in neuromuscular 
disorders have made this fruitful discovery, an Institute grantee 
has demonstrated that if a diet deficient in caoline is fed to rats 
for more than 70 days it produces the symptoms of muscular dystrophy, 
thereby providing still another lead for clinical research in this 
disease. 

These and other advances are beginidng to supply some of the 
impoi^tant missing parts in the puzijle of our knowledge about muscular 



- 22 - 

dystrophy and neuromuscular disorders. Tiie a;";.dition of a fevi rnore 
parts should enable Institute investigators to fit the pieces together 
for a rational explanation and ultimate preveiition or control of these 
disorders. 
CATAttaCT 

Previous attempts to elucidate the cause of cataractj a disorder 
marked by partial or complete opacity of the lens of the eye and re- 
sponsible for more than 20 percent of the blindness in the Urjited 
States, have largely been restricted to chemical or physical analysis 
of the lens after cataract has formed. This approach has not been 
fruitful in determining the changes in lens composition occuring ■ 
with the formation and growth of cataract, and it is now to the 
problem of cataract as a function of growth and aging of the lens 
that several scientists, both here at Bethesda and at other labora- 
tories, are addressing themselves. 

It is possible to cause experimental cataract in animals by 
administration of the compound alloxan, a simple method of obtaining 
and examining the lens at all stages of cataract formation has been 
ds'''ic3d by a grantee through sacrifice oi experimental animals with 
cataract at various time intervals during cataract development. On 
the basis of 108 lens obtained from Sk experimental rats, the 
pathological sequence of events leading to lens opacity has been 
established, and it is expected further studies will illuminate the 
key biochemical alteraticns involved. 



- 23 - 

The method by iirhich alloxan causes cataract may also shed light 
on its development, and tiiis approach has been initiated at the insti- 
tute. That alloxan interferes ^^rith several ocular enzyme systems 
is already known, and it has been confirmed that alloxan has an 
affinity with the important sulfhydrl groups within the eye, U"hat 
properties of all.oxan, however, are likely to influence these enzjniie 
sj^'stems to cause cataract have yet to be clarified, and attempts, 
therefore, to isolate these properties are now being made. 

Experimental cataract may also be created through X-ray 
irradiation, and another node of attack broached by the Institute 
lies in the search for agents wliich can block this occurrence. An 
amino acid called cystine has been found to have some inhibiting 
effect on the formation of cataract when a applied to the eye prior 
to irradiation, and exploration of this finding may illuminate the 
chemistry of prevention and eventually suggest the clinical raeans 
for treatment, 
OTHLii P.uOG...ESS 

The review of research developments in the neuroloj^ical and 
sensory disorders might be extended indefinitely. Some achievements 
are not applicable to the larger categories of neui^ological and 
sensory disease, though in some instances thej'' may well be as 
important. These and other achievements are hereby listed, mth 
further elaboration to be found in the institute's Highlights for 
19i^l+. 



. 2U - 



Discovery of a r!;Gtuod for measurement cf local cerebral blood 
floi^ in animals viith potential application for hun^ans opens 
up a new avenue for attack on the treatment and prevention 
of cei'fcbral vascular disease (stroke) . 

Further li^ht is being shed on the causes of peptic ulcer 
in studies indicating the role of the hypothalamus and the 
pituitary adrenal system in the secretion of gastric hydro- 
chloric acid. 

Evidence has been produced that "intellectual deficits" may 
be produced by lesions occurring in any portion of the 
cerebral hemispheres 3 not chiefly by frontal lobe involvement 
as previously believed. 

The neurological mechanisms involved in the postural and move- 
ment control of mammals have been elucidated^ thereby 
illuminating further areas in the pathology of cerebral 

palsy. 

It has I'Gcently been found that diabetic retinopathy, a 
leading cause of blindness, is not directly related to the 
severity of diabetss;^ it is a special disease of the eye and 
kidney^ in which the metabolism of vitamin B-12 is affected. 

A pupillograpliic machine has been developed which can measure 
and record continuous minute changes in the eye's pupilj 
thereby providing an invaluable tool for early diagnosis of 
many eye and nervous disorders. 

A surgical procedure has been devised for the relief of severe 
cases of Parkinson's Disease (shaking palsy). 

Calcific corneal opacities j such as result from certain burns 
and diseases, can now be dissolved by means of a neutral 
solution of the sodium salt of ethylene dianine tetraacetic 
acid. ^ 

A new eye chart has been devised in which the type faces now 
provide a maximum recognition factor and a minimum of confusion. 

It has been found that the possibility of fatality in brain 
surgery is frequently heralded by gastrointestinal hemorrhage 
and ulceration, calling for replacement therapy, administration 
of vitaiiiin K and, possibly, autonomic blocking agents. 



25 



BaL (253-dimercaptoproponal) Of Versene have been found 
effective in the treatment of Wilson's Disease j a disorder 
marked by progressive tremor, rigidity and mental deteriora- 
tion. 

Nasophar-.Tigeal irradiation has been found markedly effective 
for the reduction of lymphoid tissue in the naso_jhar.'/n:c, the 
major cause of hearing deficit in cnaldren. 

KEoEAJtlCH AIID TKAlNlNG oUpPOivC 

« 

•GiUKITS 

1 

That increased support of research in the neurological and 
sensory disorders nas resulted in significant gi'ant research achieve- 
ment has already been ar.ply revealed, in jast years, such sup;jort 
was relatively slight and the demand foi' research grants far e.cceeded 
the institute's ability bo make them available. 

In 19Sh, this situation was partially met by an increase of 
appropriations, idiich jermitted the a^^f^.rd of 285 research grants in 
the amount of •;?2,8l3j222. During this present year, with two of the 
three Council meetings so far held for tlie approval of grants, ire. 
have already been able to award 338 grants for ,)3 , l|.U2 , 206 . "' '/Jith 
the continued increase of potential in neurological and sensory 
disease research, it is clear that the next Council meeting -.dil lind 
investigators with approved research projects more than r-ieeting the 
total appropriation of >3, 900,000, 

TRaiMiNG 

Testimony in oast years has indicated that one of the largest 
gap areas has been the need for better iac3 lities in the graduate 

■'''A :)pendix C - Grant Support hy Disease or Disoi'der 



- 26 - 

training of clinical teachers and researchers in neiirological and 
sensory disorders. Up until 195h) less than one-tliird of all the 
country's medical schools had complete neurological units for teach- 
ing physicians and scientistsj many neurological teachers were not 
qualified ne\irologistsj and, indeed, in several States in the United 
States there was not a single qualified neurologist, teacher or other- 
wise. In ophthalmology, while 150 specialists are being trained each 
year, 300 are dying or retiring, and yet the general population 
continues to swell steadily. 

This situation is now being remedied. It began in 195Uj 
where an initial budget of !i>l400,000 for training grants enabled us 
to support 23 such programs. At this time this year, vjb have 
already been able to support [|.0 of them at a cost of $712, UU?^ with 
the total appropriation for the year of (1^900,000 already committed."*^ 

The same manifestation of the gathering importance of training 
is revealed in every category of the training program. As of January 1, 
1955 J 28 pre- and post-doctorate fellowships had been awarded, but 
enough requests were already on hand to meet the total appropriation 
of ^150,000, Again, 28 traineeships for $92,l4l40 have been awarded, 
but 18 other qualified requests already exceed the appropriation of 
$10[|.,000 for this purpose. 



""'Appendix D - Training grant support ' by medical schools. 



Appendix A 



- 27 - 



J'iEDICAL SCHOOLS aFD FRITTGIPAL li-WfiSTIlKTORS 
PARTICIPATING IN EPIIiiPSI STUDIES VJITH ASFARAGINE 



1) Children's Medical Center (Harvard Medical School) 

Boston, Massachusetts 
Dr. Charles Davidson 

2) University of North Carolina Medical School 

Chapel Hill, North Carolina 
Dr. Thomas Farmer 

3) University of Virginia Medical School 

Charlottesville, Vjjrginia 
Dr. Ualter K lineman 

h) University of Buffalo Medical School 
Biiff alo, New York 
Dr. Bernard Sj.iith 

5) University of Maryland Medical School 
Baltimore, l%ryland 
Dr. Charles Van Bus kirk 



Appendix B - 2b 



REVIEVJ OF PRELIICNARY STATISTICS EMERGING 
FROM COLLABORATIVE STUDY OF RETROLENTAL FIBROPLASIA 



1) Of 53 infants in 18 hospitals receiving routine oxyp;en 
in their incubators, 72 percent incurred retrolental 
fibroplasia, with 25 percent permanently blinded. 

2) Of 2li5 infants, however, who had received curtailed 
oxygen (for clinical crisis only), only 30 percent 
developed the disease and less than 6 j^ercent suffered 

loss of vision."" / 



3) The mortality rate was 22.2 percent in routine oxygen 
and 20sl percent for those in curtailed, indicating, 
contrary to fears, that diminution of oxygen did not 
increase the death rate. 



\ 



*It is believed that even fewer cases will now occi'r because 
of indications for greater caution due to the finding that 
oxygen administration for even so short a period as three 
days may cause retrolental fibroplasia. 



29 



Appendix C 
RESEARCH GRANT SUPPORT BY CATEGORY OF DISEASE OR DISORDER 



I. NEUROLOGIC DISORDERS 



19glt 
No. Amount 



No , Amount 



A. Cerebral Palsy and 
Chronic Cerebral 
Disorders 

B. Epilepsy & Other 
Paroxysmal Cerebral 
Disorders 

C. Multiple Sclerosis 
& Denyelinating 
Diseases 

D. Muscular Dystrophy 
& Neuromuscular 
Disorders 

E. General Metabolic & 
Deficiency Disorders 
of Nervous System 

F. Poliomyelitis & Other 
Infectious Diseases of 
the Nervous System 

G. Accident & Injury to 
the Nervous System 

H. Other Disorders of the 
Nervous System not 
Included Above 



111 - ^^k$3,986 



27 



16 



23 



3U 



27 



12 



282,I;U5 



2Ul,366 



237,U97 



368,829 



33,019 



3m, 269 



117,09li 



59 - $535,006 



31; - 536,285 



18 



U3 



23ii,060 



27 - 231,621 



392,825 



U - 35/^Q9 



3h - 2l;8,8U2 



13 - 1W;,C05 



Sub-total 189 2, 0U8, 505 



232 2,358,23: 



^Includes funds already awarded or encumbered thus far in fiscal year 1955. 



- 30 - 



195U 19^'' 

II. SENSORY DISORDERS Wo^ Amount No, Amount 

A. Disorders of Hearing 

and Balance 10 - ^ 9h,337 l6 - $17^,25? 

Sub-total 10 9k, 337 16 17U,257 

B. DisordfcxS of Vision 

1. Cataract 7 - S3, 09$ 6 - l46,l471 

2. Glaucoma 9 - 109, 26U 11 - 127,1^6 

3. Retinopathy h - 38,898 9 - l)4l,503 
U. Retrolental Fibroplasia l6 - 6l,ii90 10 - 83,06l 

5, Uveitis J Keratitis, 

& Other Inflammatory 

& Parasitic Diseases 6 - 57,8^9 9 - 96,280 

6. Metabolic & Degenera- 

tive Diseases of the 

Eye 22 - l6l,l8U 20 - 199,691; 

7, Strabismus & Neuro- 

muscular Disorders 2 - 3,381 2 - 9,C62 

8. Other Ophthalmic 

Disorders Including 

Injuries 5 - l|0,35l4 h - 32,^81 



Sub-total 71 525,525 71 735,708 

G. Disorders of the Other 
Special Senses (taste, 
smell, touch, & pain) l5 - liil,855 19 - 171;, OO8 

Sub-total 15 1^1,855 19 17U,008 



GRAND TOTAL 28U 2,810,222 338 3,14^2,206 
'Includes funds already awarded or eiicmnbered thus far in fiscal year 1955. 



Appendix D 

C-RADmTE MEDICAL TR/iININQ GR/iNTS 

ACTIVE AS OF FEBRUARY 1, 19'^S 



- 31 



Instit-utio n 

California 
University of California 

Connecticut 

Yale University- 
District of Columbia 

Georgetown University 

Georgia 
Emory University 

Illinois 
University of Chicago 

Illinois 
Northwestern University 

Iowa 
State University of Iowa 

Kansas . 
University of Kansas 

Kentucky 
University of Louisville 

Maryland 
The Johns Hopkins University 

Maryland 
University of fferyland 

Massachusetts 
Harvard University 

Massachusetts 
Harvard University 

Massachusetts 
Tufts College 



Type 



Neurologic disorders 



A mount 
;!^lU,U30 
Jk>h90 
21,393 
17,280 
19,030 
19,600 
21,621 
Hi, 050 

21,600 
20,520 
20,962 
5,751 
8,Ul 
13,500 



Neurolo!?:ic disorders 



32 - 



Michigan 
University of MichiE^an " " $18,U68 

Minnesota 
University of Minnesota » " 17,8[|.3 

Missouri 
Washington University " " lU,705 

New York 
Albany Medical College « " 13', 111 

New York 
University of Buffalo '"" "■ l6,k96 

New York 
Columbia University " " 12,975 

New York 
Columbia University " " 19,iil3 

New York 
State University of New York " " 8,807 

New York 
Montefiore Hospital ':" " 16,200 

New York 
The Mount Sinai Hospital » " 15,120 

New York 
New York University " " 15,279 

North Carolina 
University cxf North Carolina " " lit, 020 

North Carolina 
Bowman 'dray, School of Medicine " " 15,000 

Oregon 
University of Oregon " » 16,992 

Utah 
University of Utah " » 21,020 

Vermont 
University of Vermont it it lli,700 



- 33 



Institution 



Type 



Amount 



Louisiana 
Tvilane University Ophthalmic disorders $18,^89 


Maryland 
The Johns Hopkins University " 


" 65, 19h 


Massachusetts 
Harvard Medical School " 


" 23,809 


District of Coliwibia 
Episcopal Eye, Ear 
and Throat Hospital " 


" U,978 


Mi.ssouri 
Washington University " 


" 15,1^00 


New York 
Cornell University " 


" 9,828 


North Carolina 
University of North Carolina " 


" 20,SU2 


Ohio 
Ohio State University " 


12,550 


Ohio 
Western Reserve University " 


" 26,U60 


Oregon 
University of Oregon " 


" 25,000 


Pennsylvania 
Wills Eye Hospital " 


» 18,830 



ffttiry 

Naiiontt rnstitutes ol Health 

Bethesda 14, Maryland 




NIH LIBRARY 
4 0109 9699 



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00005 7904 



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